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Purpose: In recent years, several new targeted therapies have emerged for advanced breast cancer (aBC). However, real-life data specific to aBC and different breast cancer subtypes are scarce. This retrospective cohort study was designed to describe the distribution of aBC subtypes, incidence, treatment patterns, survival, and PIK3CA hotspot mutation frequency. Methods: The study included all patients in the Hospital District of Southwest Finland diagnosed with aBC between 2004 and 2013 and with a sample available in Auria Biobank. In addition to registry-based data collection, 161 HR+/HER2− aBCs were screened for PIK3CA mutations. Results: Altogether, 54.7% of the 444 patients included in the study had luminal B subtype. The smallest representations were in HR−/HER2+ (4.5%) and triple-negative (5.6%) subgroups. The percentage of aBC among all diagnosed breast cancers increased until 2010, after which it remained stable. The triple-negative cancers were associated with shorter median overall survival (5.5 months) compared to other subgroups (16.5–24.6 months). Most (84%) triple-negative cancers also metastasized during the first two years, whereas this was more evenly distributed over time in other subgroups. Of the HR+/HER2− tumors, 32.3% harbored a PIK3CA hotspot mutation. These patients, however, did not have inferior survival compared to patients with PIK3CA wild-type cancers. Conclusion: This study described real-world aBC subgroups and indicated that the clinical outcomes of subgroups vary. Although PIK3CA hotspot mutations did not lead to inferior survival, they are relevant as possible treatment targets. Overall, these data could be utilized to further evaluate the subgroup-specific medical needs in breast cancer. [ABSTRACT FROM AUTHOR]

Purpose: Constituting 15 to 20% of breast cancer cases, the triple-negative subtype lacks effective treatments as being less responsive to hormone-associated therapies. Alternatively, a more powerful immunotherapeutic vaccination can trigger immune recognition and destruction against breast cancer by incorporating oncological antigens such as human epidermal growth factor receptor 2 (HER2/neu). Currently, HER2/neu-based vaccines have finished three phases with breast cancer patients, in conjunction with granulocyte-macrophage colony-stimulating factor (GM-CSF) that was proven to be a promising vaccine adjuvant in other cancer trials previously. Methods: Completed HER2/neu-based vaccine trials with GM-CSF immunoadjuvants for breast cancer were summarised, and additionally, the article discussed prominent findings of vaccine effectiveness in triple-negative breast cancer, regarding li-Key hybrid in vaccine design and co-administration of anti-HER2/neu trastuzumab. Results: Nine clinical trials of three HER2/neu epitopes, one with li-Key hybrid, were analysed with or without the presence of trastuzumab. Immunological responses and minimal toxicities were observed in these epitopes, and disease-free survival was especially improved in the triple-negative population. Conclusion: HER2/neu-based peptide vaccine is a safe and effective approach against breast cancer, and its benefits can be potentially furthered by combining the li-Key hybrid vaccine with targeted drugs and adjuvants selected to enhance cross-presentation for exogenous vaccine antigens. [ABSTRACT FROM AUTHOR]

In recent years, laser photothermal therapy of cancers, as a new adjuvant treatment, has attracted a lot of attention. Nanoparticles have been applied to increase the effect of plasmonic photothermal therapy (PPTT) with decreasing side effects. Plasmonic photothermal therapy using gold nanoparticles (Au NPs) has been employed as a novel approach for PPTT. In this research, Au NPs were green synthesized by utilizing Rutin extract as a stabilizing and reducing agent. Afterward, structural and physical characteristics were evaluated by the use of transmission electron microscopy (TEM), and visible–ultraviolet spectrophotometer (UV–Vis). Biocompatibility and cytotoxicity of nanoparticles are tested using the MTT method. The therapeutic effect of this nanoparticle on breast cancer cells was investigated in vitro using a laser with a power of 500 mW and a wavelength of 532 nm. Microscopic images revealed that the synthesized Au NPs had the mean size of 40 nm and a roughly spherical form. The results indicate the selective and effective anticancer function of Ru-Au NPs, in addition to low cytotoxicity and better biocompatibility for normal cells. Also, the findings demonstrate the significant efficacy of Ru-Au NPs coupled with laser radiation (150 J/cm2 of laser energy for 300 s) in the treatment of breast cancer MCF-7 cells. As a result of the study, an ecoenvironmental nanoplatform for PPTT against MCF-7 human breast cancer cell line with excellent anticancer function and acceptable biocompatibility has been developed. [ABSTRACT FROM AUTHOR]

Several international and national consensus guidelines from professional bodies and expert panels are available for the management of breast cancers. The widely used international guidelines are from the National Comprehensive Cancer Network (NCCN), St. Gallen International Expert Consensus, and the European Society of Medical Oncology (ESMO) and the National Institute for Health and Care Excellence (NICE) of the UK. This article is an update from the Association of Breast Surgeons of India (ABSI) regarding the guidelines to manage breast cancer in India. The earlier version of the same was published in 2016. This article has been updated with the latest research work in the management of breast cancer to date and necessary changes made to the earlier version. [ABSTRACT FROM AUTHOR]

Immune checkpoint blockade, an immunotherapy, has been applied in multiple systemic malignancies and has improved overall survival to a relatively great extent; whether it can be applied in breast cancer remains unknown. We endeavored to explore possible factors that may influence immunotherapy outcomes in breast cancer using several public databases. The possible treatment target TNF superfamily member 4 (TNFSF4) was selected from many candidates based on its abnormal expression profile, survival-associated status, and ability to predict immune system reactions. For the first time, we identified the oncogenic features of TNFSF4 in breast carcinoma. TNFSF4 was revealed to be closely related to treatment that induced antitumor immunity and to interact with multiple immune effector molecules and T cell signatures, which was independent of endocrine status and has not been reported previously. Moreover, the potential immunotherapeutic approach of TNFSF4 blockade showed underlying effects on stem cell expansion, which more strongly and specifically demonstrated the potential effects of applying TNFSF4 blockade-based immunotherapies in breast carcinomas. We identified potential targets that may contribute to breast cancer therapies through clinical analysis and real-world review and provided one potential but crucial tool for treating breast carcinoma that showed effects across subtypes and long-term effectiveness. [ABSTRACT FROM AUTHOR]

This study explored the dosimetric difference between hypofractionated whole-breast irradiation (HFWBI) with sequential boost (SEB) and simultaneous integrated boost (SIB) based on supine and prone positions to identify the superior boost mode and superior position. Thirty breast cancer patients eligible for HFWBI after breast-conserving surgery were enrolled. All patients underwent 3DCT simulation scanning in both supine and prone positions. For the SEB-HFWBI plan, the dose prescribed for the planning target volume (PTV) of whole breast (WB) was 2.67 Gy per fraction with a total of 15 fractions, followed by a sequential boost of 3.2 Gy per fraction to the PTV of tumor bed (TB) in 3 fractions. For the SIB-HFWBI plan, the dose prescribed for the PTV of WB was 2.67 Gy per fraction with a total of 15 fractions, with a simultaneously integrated boost of 3.2 Gy per fraction to the PTV of TB with a total of 15 fractions. Regardless of the position, for the PTV of TB, the conformal index (CI) in the SIB-HFWBI plans was greater than those in the SEB-HFWBI plans (T = − 8.114, − 8.114; both P < 0.05). The CI for the PTV of WB increased significantly in the prone position relative to the supine position in both two plans(Z = − 3.340, − 3.501; all P < 0.05). The study suggested that prone SIB-HFWBI might be more suitable for postoperative radiotherapy after breast-conserving surgery for early-stage breast cancer patients. [ABSTRACT FROM AUTHOR]

Whole-genome doubling (WGD) is an early macro-evolutionary event in tumorigenesis, involving the doubling of an entire chromosome complement. However, its impact on breast cancer subtypes remains unclear. Here, we performed a comprehensive and quantitative analysis of WGD and its influence on breast cancer subtypes in patients from Taiwan and consequently highlight the genomic association between WGD and homologous recombination deficiency (HRD). A higher manifestation of WGD was reported in triple-negative breast cancer, conferring high chromosomal instability (CIN), while HER2 + tumors exhibited early WGD events, with widely varied CIN levels, compared to luminal-type tumors. An association of higher activity of de novo indel signature 2 with WGD and HRD in Taiwanese breast cancer patients was reported. A control test between WGD and pseudo non-WGD samples was further employed to support this finding. The study provides a better comprehension of tumorigenesis in breast cancer subtypes, thus assisting in personalized treatment. Wu, Hsieh et al. analyze Taiwanese breast cancer patient samples using whole-exome sequencing to examine the heterogeneity and homogeneity in the timing and dependencies of somatic aberrations across disease subtypes. The authors focus on somatic alterations and related features that correlate with whole genome doubling, including homologous recombination deficiencies. [ABSTRACT FROM AUTHOR]

Ferroptosis is a new form of regulated cell death (RCD), and its emergence has provided a new approach to the progression and drug resistance of breast cancer (BRCA). However, there is still a great gap in the study of ferroptosis-related genes in BRCA, especially luminal-type BRCA patients. We downloaded the mRNA expression profiles and corresponding clinical data of BRCA patients from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) and The Cancer Genome Atlas (TCGA) databases. Then, we built a prognostic multigene signature with ferroptosis-related differentially expressed genes (DEGs) in the METABRIC cohort and validated it in the TCGA cohort. The predictive value of this signature was investigated in terms of the immune microenvironment and the probability of a response to immunotherapy and chemotherapy. The patients were divided into a high-risk group and a low-risk group according to the ferroptosis-associated gene signature, and the high-risk group had a worse overall survival (OS). The risk score based on the 10 ferroptosis-related gene-based signature was determined to be an independent prognostic predictor in both the METABRIC and TCGA cohorts (HR, 1.41, 95% CI, 1.14–1.76, P = 0.002; HR, 2.19, 95% CI, 1.13–4.26, P = 0.02). Gene set enrichment analysis indicated that the term "cytokine-cytokine receptor interaction" was enriched in the high-risk score subgroup. Moreover, the immune infiltration scores of most immune cells were significantly different between the two groups, the low-risk group was much more sensitive to immunotherapy, and six drugs might have potential therapeutic implications in the high-risk group. Finally, a nomogram incorporating a classifier based on the 10 ferroptosis-related genes, tumor stage, age and histologic grade was established. This nomogram showed favorable discriminative ability and could help guide clinical decision-making for luminal-type breast carcinoma. [ABSTRACT FROM AUTHOR]

The current study aims to assess the effect of cone beam computed tomography (CBCT) frequency during adjuvant breast cancer radiotherapy with simultaneous integrated boost (SIB) on target volume coverage and dose to the organs at risk (OAR). 50 breast cancer patients receiving either non-hypofractionated or hypofractionated radiotherapy after lumpectomy including a SIB to the tumor bed were selected for this study. All patients were treated in volumetric modulated arc therapy (VMAT) technique and underwent daily CBCT imaging. In order to estimate the delivered dose during the treatment, the applied fraction doses were recalculated on daily CBCT scans and accumulated using deformable image registration. Based on a total of 2440 dose recalculations, dose coverage in the clinical target volumes (CTV) and OAR was compared depending on the CBCT frequency. The estimated delivered dose (V95%) for breast-CTV and SIB-CTV was significantly lower than the planned dose distribution, irrespective of the CBCT-frequency. Between daily CBCT and CBCT on alternate days, no significant dose differences were found regarding V95% for both, breast-CTV and SIB-CTV. Dose distribution in the OAR was similar for both imaging protocols. Weekly CBCT though led to a significant decrease in dose coverage compared to daily CBCT and a small but significant dose increase in most OAR. Daily CBCT imaging might not be necessary to ensure adequate dose coverage in the target volumes while efficiently sparing the OAR during adjuvant breast cancer radiotherapy with SIB. [ABSTRACT FROM AUTHOR]

Breast cancer clinical treatment selection is based on the immunohistochemical determination of four protein biomarkers: ESR1, PGR, HER2, and MKI67. Our aim was to correlate immunohistochemical results to proteome-level technologies in measuring the expression of these markers. We also aimed to integrate available proteome-level breast cancer datasets to identify and validate new prognostic biomarker candidates. We searched studies involving breast cancer patient cohorts with published survival and proteomic information. Immunohistochemistry and proteomic technologies were compared using the Mann–Whitney test. Receiver operating characteristics (ROC) curves were generated to validate discriminative power. Cox regression and Kaplan–Meier survival analysis were calculated to assess prognostic power. False Discovery Rate was computed to correct for multiple hypothesis testing. We established a database integrating protein expression data and survival information from four independent cohorts for 1229 breast cancer patients. In all four studies combined, a total of 7342 unique proteins were identified, and 1417 of these were identified in at least three datasets. ESR1, PGR, and HER2 protein expression levels determined by RPPA or LC–MS/MS methods showed a significant correlation with the levels determined by immunohistochemistry (p < 0.0001). PGR and ESR1 levels showed a moderate correlation (correlation coefficient = 0.17, p = 0.0399). An additional panel of candidate proteins, including apoptosis-related proteins (BCL2,), adhesion markers (CDH1, CLDN3, CLDN7) and basal markers (cytokeratins), were validated as prognostic biomarkers. Finally, we expanded our previously established web tool designed to validate survival-associated biomarkers by including the proteomic datasets analyzed in this study (https://kmplot.com/). In summary, large proteomic studies now provide sufficient data enabling the validation and ranking of potential protein biomarkers. [ABSTRACT FROM AUTHOR]

Three cyclin-dependent kinases 4/6, including palbociclib, ribociclib, and abemaciclib, have been approved for the treatment of patients with hormone receptor-positive and human epidermal growth factor receptor 2-negative advanced breast cancer. The objective of this study was to evaluate the occurrence and clinical spectrum of cutaneous adverse events in patients with breast cancer following therapy with cyclin-dependent kinase 4/6 inhibitors. A systematic literature search was performed in the PubMed, Cochrane, and EMBASE databases up to November 2020 to evaluate studies published from 2015 to 2020. Articles were selected by title, abstract, and full text as required. In addition, a manual search was performed from among the references of articles included. Forty-one articles were included with a total of 13 reported dermatologic reactions including alopecia, bullous skin rash, Stevens–Johnson syndrome, toxic epidermal necrolysis, radiation recall and radiation dermatitis, Henoch–Schonlein purpura, cutaneous leukocytoclastic vasculitis, subacute and chronic cutaneous lupus erythematosus, histiocytoid Sweet syndrome, vitiligo-like lesions, and erythema dyschromicum perstans. Skin toxicity is an important issue because it usually affects a patient's quality of life and could lead to a discontinuation of therapies; therefore, it is of fundamental importance to recognize and adequately manage the adverse skin reactions associated with these types of drugs. [ABSTRACT FROM AUTHOR]

Three-dimensional cell culture platforms based on decellularised patient-based microenvironments provide in vivo-like growth conditions allowing cancer cells to interact with intact structures and components of the surrounding tissue. A patient-derived scaffold (PDS) model was therefore evaluated as a testing platform for the endocrine therapies (Z)-4-Hydroxytamoxifen (4OHT) and fulvestrant as well as the CDK4/6-inhibitor palbociclib, monitoring the treatment responses in breast cancer cell lines MCF7 and T47D adapted to the patient-based microenvironments. MCF7 cells growing in PDSs showed increased resistance to 4OHT and fulvestrant treatment (100- and 20-fold) compared to 2D cultures. Quantitative PCR analyses of endocrine treated cancer cells in PDSs revealed upregulation of pluripotency markers further supported by increased self-renewal capacity in sphere formation assays. When comparing different 3D growth platforms including PDS, matrigel, gelatin sponges and 3D-printed hydrogels, 3D based cultures showed slightly varying responses to fulvestrant and palbociclib whereas PDS and matrigel cultures showed more similar gene expression profiles for 4OHT treatment compared to the other platforms. The results support that the PDS technique maximized to provide a multitude of smaller functional PDS replicates from each primary breast cancer, is an up-scalable patient-derived drug-testing platform available for gene expression profiling and downstream functional assays. [ABSTRACT FROM AUTHOR]

ConvitVax is a personalized vaccine for the treatment of breast cancer, composed of autologous tumor cells, bacillus Calmette-Guérin (BCG) and low concentrations of formalin. Previous pre-clinical studies show that this therapy induces a potent activation of the immune system and achieves an effective response against tumor cells, reducing the size of the tumor and decreasing the percentage of immunosuppressive cells. In the present study, we evaluate the toxicity of ConvitVax in healthy BALB/c mice to determine potential adverse effects related to the vaccine and each of its components. We used standard guidelines for pain, discomfort and distress recognition, continuously evaluated the site of the injection, and completed blood and urine clinical tests. Endpoint necropsy was performed, measuring the weight of organs and processing liver, kidney, thymus and lung for histological examination. Results show that the vaccine in its therapeutic dose, at 3 times its therapeutic concentration, and its individual components did not cause death or behavioral or biological changes, including any abnormalities in whole-body or organ weights, and tissue damage. These results support the safety of ConvitVax with minimal to no side-effects. [ABSTRACT FROM AUTHOR]

Triple-negative breast cancer (TNBC) is a highly malignant type of breast cancer and lacks effective therapy. Targeting cysteine-dependence is an emerging strategy to treat the mesenchymal TNBC. However, many TNBC cells are non-mesenchymal and unresponsive to cysteine deprivation. To overcome such resistance, three selective HDAC6 inhibitors (Tubacin, CAY10603, and Tubastatin A), identified by epigenetic compound library screening, can synergize with cysteine deprivation to induce cell death in the non-mesenchymal TNBC. Despite the efficacy of HDAC6 inhibitor, knockout of HDAC6 did not mimic the synthetic lethality induced by its inhibitors, indicating that HDAC6 is not the actual target of HDAC6 inhibitor in this context. Instead, transcriptomic profiling showed that tubacin triggers an extensive gene transcriptional program in combination with erastin, a cysteine transport blocker. Notably, the zinc-related gene response along with an increase of labile zinc was induced in cells by the combination treatment. The disturbance of zinc homeostasis was driven by PKCγ activation, which revealed that the PKCγ signaling pathway is required for HDAC6 inhibitor-mediated synthetic lethality. Overall, our study identifies a novel function of HDAC6 inhibitors that function as potent sensitizers of cysteine deprivation and are capable of abolishing cysteine-independence in non-mesenchymal TNBC. [ABSTRACT FROM AUTHOR]

The epithelial–mesenchymal transition (EMT) imparts properties of cancer stem-like cells, including resistance to frequently used chemotherapies, necessitating the identification of molecules that induce cell death specifically in stem-like cells with EMT properties. Herein, we demonstrate that breast cancer cells enriched for EMT features are more sensitive to cytotoxicity induced by ophiobolin A (OpA), a sesterterpenoid natural product. Using a model of experimentally induced EMT in human mammary epithelial (HMLE) cells, we show that EMT is both necessary and sufficient for OpA sensitivity. Moreover prolonged, sub-cytotoxic exposure to OpA is sufficient to suppress EMT-imparted CSC features including sphere formation and resistance to doxorubicin. In vivo growth of CSC-rich mammary cell tumors, is suppressed by OpA treatment. These data identify a driver of EMT-driven cytotoxicity with significant potential for use either in combination with standard chemotherapy or for tumors enriched for EMT features. [ABSTRACT FROM AUTHOR]

The novel procedure of few-layer black phosphorus (FLBP) stabilization and functionalisation was here proposed. The cationic polymer PLL and non-ionic PEG have been involved into encapsulation of FLBP to allow sufficient time for further nanofabrication process and overcome environmental degradation. Two different spacer chemistry was designed to bind polymers to tumor-homing peptides. The efficiency of functionalisation was examined by RP-HPLC, microscopic (TEM and SEM) and spectroscopic (FT-IR and Raman) techniques as well supported by ab-initio modelling. The cell and dose dependent cytotoxicity of FLBP and its bioconjugates was evaluated against HB2, MCF-7 and MDA-MB-231 cell lines. Functionalisation allowed not only for improvement of environmental stability, but also enhances therapeutic effect by abolished the cytotoxicity of FLBP against HB2 cell line. Moreover, modification of FLBP with PLL caused increase of selectivity against highly aggressive breast cancer cell lines. Results indicate the future prospect application of black phosphorus nanosheets as nanocarrier, considering its unique features synergistically with conjugated polymeric micelles. [ABSTRACT FROM AUTHOR]

HER2 and HER3 play key driving functions in the pathophysiology of HER2-amplified breast cancers, but this function is less well characterized in other cancers driven by HER2 amplification. This study aimed to explore the role of HER2 and HER3 signaling in other types of HER2-amplified cancer. The expression and signaling activity of HER2, HER3, and downstream pathway proteins were studied in cell panels representing HER2-amplified cancers of the breast, bladder, colon and rectal, stomach, esophagus, lung, tongue, and endometrium along with controls lacking HER2 amplification. We report that HER2-amplified cancers are addicted to HER2 across different cancer types and the depth of addiction is best linked with the expression level of HER2, but not with HER3 expression. We report that the expression and constitutive phosphorylation of HER3 are ubiquitous in HER2-amplified breast cancer cell lines, but much more variable in HER2-amplified cancer cells from other tissues. We observed the lapatinib-induced compensatory upregulation of HER3 signaling in many types of HER2-amplified cancers, although with much variability. We find that HER3 expression is essential for in vivo tumorigenic growth in some HER2-amplified tumors but not others. Importantly HER3 expression level does not correlate well with its functional importance. More biomarkers will be needed to guide the optimal use of HER3 inhibitors in HER2-amplified cancers from non-breast origin. Unlike oncogenes activated through mutational events, the activation of HER2 through overexpression represents a gradient of activities and depth of addiction and the response to inhibitors follows a similar gradient. [ABSTRACT FROM AUTHOR]

Extreme responders to anticancer therapy are rare among advanced breast cancer patients. Researchers, however, have yet to investigate treatment responses therein on the whole exome level. We performed whole exome analysis to characterize the genomic landscape of extreme responders among metastatic breast cancer patients. Clinical samples were obtained from breast cancer patients who showed exceptional responses to anti-HER2 therapy or hormonal therapy and from those who did not. Matched breast tumor tissue (somatic DNA) and blood samples (germline DNA) were collected from a total of 30 responders and 15 non-responders. Whole exome sequencing using Illumina HiSeq2500 was performed for all 45 patients (90 samples). Somatic single nucleotide variants (SNVs), indels, and copy number variants (CNVs) were identified for the genomes of each patient. Group-specific somatic variants and mutational burden were statistically analyzed. Sequencing of cancer exomes for all patients revealed 1839 somatic SNVs (1661 missense, 120 nonsense, 43 splice-site, 15 start/stop-lost) and 368 insertions/deletions (273 frameshift, 95 in-frame), with a median of 0.7 mutations per megabase (range, 0.08 to 4.2 mutations per megabase). Responders harbored a significantly lower nonsynonymous mutational burden (median, 26 vs. 59, P = 0.02) and fewer CNVs (median 13.6 vs. 97.7, P = 0.05) than non-responders. Multivariate analyses of factors influencing progression-free survival showed that a high mutational burden and visceral metastases were significantly related with disease progression. Extreme responders to treatment for metastatic breast cancer are characterized by fewer nonsynonymous mutations and CNVs. Lim, Kim and Jung et al. report a whole-exome sequence analysis of 30 Korean patients showing extreme treatment responses for metastatic breast cancer. They find that compared to non-responders, extreme responders have fewer nonsynonymous mutations and copy number variants. [ABSTRACT FROM AUTHOR]

The functionalization of liposomes with monoclonal antibodies is a potential strategy to increase the specificity of liposomes and reduce the side-effects associated with chemotherapeutic agents. The active targeting of the Human Epidermal growth factor Receptor 2 (HER2), which is overexpressed in HER2 positive breast cancer cells, can be achieved by coating liposomes with an anti-HER2 monoclonal antibody. In this study, we synthesized calcein and Doxorubicin-loaded immunoliposomes functionalized with the monoclonal antibody Trastuzumab (TRA). Both liposomes were characterized for their size, phospholipid content and antibody conjugation. Exposing the liposomes to low-frequency ultrasound (LFUS) triggered drug release which increased with the increase in power density. Trastuzumab conjugation resulted in enhancing the sensitivity of the liposomes to LFUS. Compared to the control liposomes, TRA-liposomes showed higher cellular toxicity and higher drug uptake by the HER2 + cell line (SKBR3) which was further improved following sonication with LFUS. Combining immunoliposomes with LFUS is a promising technique in the field of targeted drug delivery that can enhance efficiency and reduce the cytotoxicity of antineoplastic drugs. [ABSTRACT FROM AUTHOR]

Photodynamic therapy (PDT) is based on special light source, photosensitizer (PS), and in the presence of oxygen. Different light sources have been used for PDT applications. Recent studies have focused on LED light sources for PDT applications due to reducing the cost of laser-based PDT and providing easy access for research laboratory or clinic facilities. LED-mediated PDT applications have shown promising results for the treatment of different types of disease. However, few studies have determined the effects of LED-based PDT on cancer cells. For the first time, the aim of this study was to explore the therapeutic effects of 5-aminolevulinic acid (5-ALA)-mediated PDT after LED irradiation on two sub-types (a poorly aggressive MCF-7 and a highly aggressive MDA-MB-231) of breast cancer cell lines. The effectiveness of 5-ALA PDT treatment was evaluated by WST-1, annexin V, and acridine orange staining with different energy levels. The LED system was specially developed with optical power and wavelength stability techniques. The system consists of user interface and embedded LED controller with real-time optic power output calibration by photodiode feedback. Our results demonstrated that the cell viability of breast cancer cells was considerably decreased a LED dose-dependent manner (P < 0.05). Additionally, a significant increase in the percentage of apoptotic cells was detected in breast cancer cells after irradiation with LED at a density of 18 and 30 J/cm2 energy. Consequently, the LED system could be effectively used for irradiation of 5-ALA in the treatment of breast cancer cells. [ABSTRACT FROM AUTHOR]

Mutational analysis of circulating tumour (ct) DNA holds promise as an effective tool to predict the course of metastatic breast cancer (MBC). In the present study we used targeted next generation sequencing of ctDNA to evaluate the impact of cancer driven mutations on the prognosis of MBC. The study included 59 oestrogen receptor-positive (ER+), HER2-negative MBC patients. Sequencing analysis was performed in ESR1, PIK3CA, ERBB2, PTEN, TP53, KRAS, HRAS, NRAS, and AR. At baseline, patients started receiving either chemotherapy (34%; n = 20) or cyclin-dependent kinase 4/6 inhibitor therapy in combination with endocrine therapy (CDK4/6i+ET; 66%; n = 39). Overall, 64.4% (n = 38) of the patients carried at least one pathogenic or likely-pathogenic mutation. Number of ctDNA mutations was significantly linked with worse progression free survival (PFS; p = 0.003) and overall survival (OS; p = 0.007). Furthermore, ctDNA load, defined by the number of mutant ctDNA molecules per mL plasma, significantly correlated with PFS (p < 0.001) and OS (p = 0.001). Furthermore, mutational status of ESR1 and TP53 significantly predicted PFS (p = 0.024 and p = 0.035, respectively) and OS (p < 0.001 and p = 0.035, respectively). These results emphasizes the clinical value of ctDNA mutational analysis in the management of advanced breast cancer. [ABSTRACT FROM AUTHOR]

Steroid receptor coactivator 3 (SRC-3/NCoA3/AIB1), is a key regulator of gene transcription and it plays a central role in breast cancer (BC) tumorigenesis, making it a potential therapeutic target. Beyond its function as an important regulator of estrogen receptor transcriptional activity, SRC-3 also functions as a coactivator for a wide range of other transcription factors, suggesting SRC-3 inhibition can be beneficial in hormone-independent cancers as well. The recent discovery of a potent SRC-3 small molecule inhibitor, SI-2, enabled the further development of additional related compounds. SI-12 is an improved version of SI-2 that like SI-2 has anti-proliferative activity in various cancer types, including BC. Here, we sought to identify gene targets, that when inhibited in the presence of SI-12, would lead to enhanced BC cell cytotoxicity. We performed a genome-scale CRISPR-Cas9 screen in MCF-7 BC cells under conditions of pharmacological pressure with SI-12. A parallel screen was performed with an ER inhibitor, fulvestrant, to shed light on both common and distinct activities between SRC-3 and ERα inhibition. Bearing in mind the key role of SRC-3 in tumorigenesis of other types of cancer, we extended our study by validating potential hits identified from the MCF-7 screen in other cancer cell lines. Using a CRISPR-based large-scale screen, Gilad et al. identify the genes that show synthetic lethality with an SRC-3 inhibitor in breast cancer cells while contrasting this with the estrogen receptor degrader fulvestrant. This study provides insights into the development of therapeutic strategies for cancer forms that involve SRC-3. [ABSTRACT FROM AUTHOR]

Although paclitaxel plus bevacizumab (PB) therapy is an effective chemotherapeutic regimen for HER2-negative advanced breast cancer (ABC), predictive markers for its effectiveness remain undefined. We investigated the usefulness of systemic immunity markers associated with lymphocytes as predictive markers for PB therapy in patients with HER2-negative ABC. We retrospectively reviewed data from 114 patients with HER2-negative ABC who underwent PB therapy from November 2011 to December 2019. We calculated the absolute lymphocyte count (ALC), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR) as representative systemic immunity markers. The time to treatment failure (TTF) and overall survival (OS) of the patients with high ALC, low NLR, and high LMR were significantly longer compared with those of the patients with low ALC, high NLR, and low LMR. A multivariable analysis revealed that high ALC, low NLR, and low PLR were independent predictors for TTF and high ALC, low NLR, and high LMR were independent predictors for OS. Systemic immunity markers were significantly associated with longer TTF and OS in patients who underwent PB therapy and may represent predictive markers for PB therapy in patients with HER2-negative ABC. [ABSTRACT FROM AUTHOR]

Genetic polymorphisms in select genes, including APOE (apolipoprotein E), COMT (Catechol-O-Methyltransferase), MDR1 (multi-drug resistance 1), BDNF (brain derived neurotrophic factor), and GST (glutathione-S-transferase), have been associated with vulnerability to cognitive impairment. In this study, we evaluated the relationship of these genetic variants to measures of brain health in patients with breast cancer, including neurocognitive testing and functional connectome analysis. Women with breast cancer (n = 83) and female healthy controls (n = 53) were evaluated. They underwent resting-state functional MRI scans and neurocognitive testing. Polymerase chain reaction (PCR) was performed on saliva samples to identify single nucleotide polymorphisms (SNPs) in candidate genes: APOE, COMT, MDR1, BDNF, and GST. Breast cancer patients treated with chemotherapy had slower processing speed (p = 0.04) and poorer reported executive function (p < 0.0001) than healthy controls. Those chemotherapy-treated patients that were APOE e4 carriers had significantly slower processing speed. A greater number of risk-related alleles was associated with poorer connectivity in the regions of the left cuneus and left calcarine. While breast cancer patients that are APOE e4 carriers may have a select vulnerability to processing speed impairments, other risk-related alleles were not found to influence cognitive test performance in this population. Conversely, regions of impaired functional connectivity appeared to be related to risk-related genetic polymorphisms in breast cancer patients. This suggests that a cancer patient's SNPs in candidate genes may influence the risk of neurotoxicity. Further study evaluating the impact of genotype on biomarkers of brain health in cancer survivors is warranted. [ABSTRACT FROM AUTHOR]

We report on a comparative dosimetrical study between deep inspiration breath hold (DIBH) and shallow breathing (SB) in prone crawl position for photon and proton radiotherapy of whole breast (WB) and locoregional lymph node regions, including the internal mammary chain (LN_MI). We investigate the dosimetrical effects of DIBH in prone crawl position on organs-at-risk for both photon and proton plans. For each modality, we further estimate the effects of lung and heart doses on the mortality risks of different risk profiles of patients. Thirty-one patients with invasive carcinoma of the left breast and pathologically confirmed positive lymph node status were included in this study. DIBH significantly decreased dose to heart for photon and proton radiotherapy. DIBH also decreased lung doses for photons, while increased lung doses were observed using protons because the retracting heart is displaced by low-density lung tissue. For other organs-at-risk, DIBH resulted in significant dose reductions using photons while minor differences in dose deposition between DIBH and SB were observed using protons. In patients with high risks for cardiac and lung cancer mortality, average thirty-year mortality rates from radiotherapy-related cardiac injury and lung cancer were estimated at 3.12% (photon DIBH), 4.03% (photon SB), 1.80% (proton DIBH) and 1.66% (proton SB). The radiation-related mortality risk could not outweigh the ~ 8% disease-specific survival benefit of WB + LN_MI radiotherapy in any of the assessed treatments. [ABSTRACT FROM AUTHOR]

A quantitative analysis of contrast-enhanced spectral mammography (CESM) enhancement was conducted for the early prediction of the pathological response after neoadjuvant chemotherapy (NAC). Retrospective analysis of the data of 111 patients was conducted, and all of them underwent NAC in our hospital and surgical resection after the end of all cycles from January 2018 to May 2019. They were divided into pathological complete response (PCR) and non-PCR groups. We determined whether a statistical difference in the percentage of CESM grey value reduction (ΔCGV) was present in the PCR and non-PCR groups and whether a statistical difference was observed in the diagnostic efficiency of craniocaudal (CC) and mediolateral oblique (MLO) view subtraction images. Independent sample t-test was used to compare different groups, the receiver operating characteristic (ROC) curve was used to compare the diagnostic efficacy of CC and MLO for pathological response after NAC, and the Delong test was used to compare the area under the ROC curve (AUC). Statistical significance was considered at P < 0.05. A statistical difference was observed in the ΔCGV in the PCR and non-PCR groups. No statistical difference was observed in the AUCs of CC and MLO view subtraction images. The ΔCGV can be used as a quantitative index to predict PCR early, and no statistical difference was observed in the diagnostic efficacy of CC and MLO view subtraction images. [ABSTRACT FROM AUTHOR]

Downregulation of the PTEN tumor suppressor transcript is frequent in breast cancer and associates with poor prognosis and triple-negative breast cancer (TNBC) when comparing breast cancers to one another. Here we show that in almost all cases, when comparing breast tumors to adjacent normal ducts, PTEN expression is decreased and the PRC2-associated methyltransferase EZH2 is increased. We further find that when comparing breast cancer cases in large cohorts, EZH2 inversely correlates with PTEN expression. Within the highest EZH2 expressing group, NOTCH alterations are frequent, and also associate with decreased PTEN expression. We show that repression of PTEN occurs through the combined action of NOTCH (NOTCH1 or NOTCH2) and EZH2 alterations in a subset of breast cancers. In fact, in cases harboring NOTCH1 mutation or a NOTCH2 fusion gene, NOTCH drives EZH2, HES-1, and HEY-1 expression to repress PTEN transcription at the promoter, which may contribute to poor prognosis in this subgroup. Restoration of PTEN expression can be achieved with an EZH2 inhibitor (UNC1999), a γ-secretase inhibitor (Compound E), or knockdown of EZH2 or NOTCH. These findings elucidate a mechanism of transcriptional repression of PTEN induced by NOTCH1 or NOTCH2 alterations, and identifies actionable signaling pathways responsible for driving a large subset of poor-prognosis breast cancers. Pappas et al. show that the combination of NOTCH and EZH2 alterations drive transcriptional repression of PTEN through reversible epigenetic modification of the PTEN promoter. These results suggest an actionable target for treating poor-prognosis breast cancer. [ABSTRACT FROM AUTHOR]

In the field of oncology research, a deeper understanding of tumor biology has shed light on the role of environmental conditions surrounding cancer cells. In this regard, targeting the tumor microenvironment has recently emerged as a new way to access this disease. In this work, a novel extracellular matrix (ECM)-targeting nanotherapeutic was engineered using a lipid-based nanoparticle chemically linked to an inhibitor of the ECM-related enzyme, lysyl oxidase 1 (LOX), that inhibits the crosslinking of elastin and collagen fibers. We demonstrated that, when the conjugated vesicles were loaded with the chemotherapeutic epirubicin, superior inhibition of triple negative breast cancer (TNBC) cell growth was observed both in vitro and in vivo. Moreover, in vivo results displayed prolonged survival, minimal cytotoxicity, and enhanced biocompatibility compared to free epirubicin and epirubicin-loaded nanoparticles. This all-in-one nano-based ECM-targeting chemotherapeutic may provide a key-enabling technology for the treatment of TNBC. [ABSTRACT FROM AUTHOR]

The biophysical properties of cells change with cancer invasion to fulfill their metastatic behavior. Cell softening induced by cancer is highly associated with alterations in cytoskeleton fibers. Changes in the mechanical properties of cytoskeletal fibers have not been quantified due to technical limitations. In this study, we used the micropipette aspiration technique to calculate and compare the viscoelastic properties of non-invasive and invasive breast cancer cells. We evaluated the mechanical properties of actin fibers and microtubules of two cancerous cell lines by using multiscale tensegrity modeling and an optimization method. Cancer invasion caused altered viscoelastic behavior of cells and the results of modeling showed changes in mechanical properties of major cytoskeleton fibers. The stiffness and viscosity constant of actin fibers in non-invasive cells were 1.28 and 2.27 times higher than those of the invasive cells, respectively. However, changes in mechanical properties of microtubules were minor. Immunofluorescent staining of fibers and their quantified distributions confirmed altered actin distribution among two cell lines, in contrast to microtubule distribution. This study highlights the function of cytoskeletal fibers in cancer progression, which could be of interest in designing therapeutic strategies to target cancer progress. [ABSTRACT FROM AUTHOR]

Introduction: Aromatase inhibitor (AI)-associated bone loss increases the risk of bone fracture and reduces patients' quality of life, making it a critical issue worldwide. We conducted a prospective non-randomized clinical trial (UMIN-CTR, UMIN 000016173) to assess the effect of denosumab on bone loss in patients treated with adjuvant AI and have previously reported the results at 12 and 24 months. This study aimed to present the results at 36 months of treatment with denosumab for osteopenia in breast cancer patients who were undergoing treatment with adjuvant AI; 36 months is the longest denosumab treatment period reported so far. Materials and methods: Patients received 60-mg denosumab subcutaneously every 6 months. Daily supplements containing 500-mg elemental calcium and at least 400 international units of vitamin D were highly recommended throughout the study period. The levels of bone mineral density (BMD) and bone turnover markers, serum tartrate-resistant acid phosphatase isoform 5b, and bone alkaline phosphatase were determined at baseline and 6, 12, 18, 24, and 36 months. Results: At 36 months, the bone mineral density of the lumbar spine, right femoral neck, and left femoral neck were found to increase by 8.8% (95% confidence interval CI 7.6–10.1), 4.3% (95% CI 3.0–5.5), and 3.1% (95% CI 2.1–4.1), respectively. No non-traumatic clinical fractures occurred in patients receiving AI and denosumab. Conclusion: Twice-yearly administration of denosumab to the breast cancer patients treated with adjuvant AI, regardless of the skeletal site, resulted in consistent increases in BMD without severe adverse events at 36 months. [ABSTRACT FROM AUTHOR]

Correctly estimating the hormone receptor status for estrogen (ER) and progesterone (PGR) is crucial for precision therapy of breast cancer. It is known that conventional diagnostics (immunohistochemistry, IHC) yields a significant rate of wrongly diagnosed receptor status. Here we demonstrate how Dempster Shafer decision Theory (DST) enhances diagnostic precision by adding information from gene expression. We downloaded data of 3753 breast cancer patients from Gene Expression Omnibus. Information from IHC and gene expression was fused according to DST, and the clinical criterion for receptor positivity was re-modelled along DST. Receptor status predicted according to DST was compared with conventional assessment via IHC and gene-expression, and deviations were flagged as questionable. The survival of questionable cases turned out significantly worse (Kaplan Meier p < 1%) than for patients with receptor status confirmed by DST, indicating a substantial enhancement of diagnostic precision via DST. This study is not only relevant for precision medicine but also paves the way for introducing decision theory into OMICS data science. [ABSTRACT FROM AUTHOR]

ORCID: 0000–0001-6019–7309. In the treatment of breast cancer, intensity-modulated radiation therapy (IMRT) reportedly reduces the high-dose irradiation of at-risk organs and decreases the frequency of adverse events (AEs). Comparisons with conventional radiotherapy have shown that IMRT is associated with lower frequencies of acute and late-onset AEs. Here, we extended a prospective, observational, single-center study of the safety of IMRT to a second investigating center. Patients scheduled for adjuvant IMRT after partial or total mastectomy were given a dose of 50 Gy (25 fractions of 2 Gy over 5 weeks), with a simultaneous integrated boost in patients having undergone conservative surgery. 300 patients were included in the study, and 288 were analyzed. The median follow-up period was 2.1 years. The 2-year disease-free survival rate [95% CI] was 93.4% [89.2–96.0%]. Most AEs were mild. The most common AEs were skin-related—mainly radiodermatitis [in 266 patients (92.4%)] and hyperpigmentation (in 178 (61.8%)). 35% and 6% of the patients presented with grade 2 acute skin and esophageal toxicity, respectively. Only 4 patients presented with a grade 3 event (radiodermatitis). Smoking (odds ratio) [95% CI] = 2.10 [1.14–3.87]; p = 0.017), no prior chemotherapy (0.52 [0.27–0.98]; p = 0.044), and D98% for subclavicular skin (1.030 [1.001–1.061]; p = 0.045) were associated with grade ≥ 2 acute AEs. In a univariate analysis, the mean dose, (p < 0.0001), D2% (p < 0.0001), D50% (p = 0.037), D95% (p = 0.0005), D98% (p = 0.0007), V30Gy (p < 0.0001), and V45Gy (p = 0.0001) were significantly associated with grade ≥ 1 acute esophageal AEs. In a multivariate analysis, D95% for the skin (p < 0.001), D98% for the subclavicular skin and low D95% for the internal mammary lymph nodes were associated with grade ≥ 1 medium-term AEs. The safety profile of adjuvant IMRT after partial or total mastectomy is influenced by dosimetric parameters. Trial registration: ClinicalTrials.gov NCT02281149. [ABSTRACT FROM AUTHOR]

Copper-67 (t1/2 = 2.58 days) decays by β− ( E β - max : 562 keV) and γ-rays (93 keV and 185 keV) rendering it with potential for both radionuclide therapy and single-photon emission computed tomography (SPECT) imaging. Prompted by the recent breakthrough of 67Cu production with high specific activity, high radionuclidic purity, and sufficient quantities, the interest in the theranostic potential of 67Cu has been rekindled. This work addresses the practicability of developing 67Cu-labeled antibodies with substantially improved quality for cancer radioimmunotheranostics. Proof of concept is demonstrated with pertuzumab, a US-FDA-approved monoclonal antibody for combination therapies of HER2-positive breast cancer. With an average number of 1.9 chelators coupled to each antibody, we achieved a two-order of magnitude increase in radiolabeling efficiency compared to literature reports. In a preclinical therapeutic study, mice (n = 4–7/group) bearing HER2+ xenografts exhibited a 67Cu-dose dependent tumor-growth inhibition from 67Cu-labeled-Pertuzumab co-administered with trastuzumab. Furthermore, greater tumor size reduction was observed with 67Cu-labeled-pertuzumab formulations of higher specific activity. The potential of SPECT imaging with 67Cu radiopharmaceuticals was tested after 67Cu-labeled-Pertuzumab administration. Impressively, all tumors were clearly visualized by SPECT imaging with 67Cu-labeled-Pertuzumab even at day 5 post injection. This work demonstrates it is practical to use 67Cu radioimmunoconjugates for cancer radioimmunotheranostics. [ABSTRACT FROM AUTHOR]

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype, lacking effective therapy. Many TNBCs show remarkable response to carboplatin-based chemotherapy, but often develop resistance over time. With increasing use of carboplatin in the clinic, there is a pressing need to identify vulnerabilities of carboplatin-resistant tumors. In this study, we generated carboplatin-resistant TNBC MDA-MB-468 cell line and patient derived TNBC xenograft models. Mass spectrometry-based proteome profiling demonstrated that carboplatin resistance in TNBC is linked to drastic metabolism rewiring and upregulation of anti-oxidative response that supports cell replication by maintaining low levels of DNA damage in the presence of carboplatin. Carboplatin-resistant cells also exhibited dysregulation of the mitotic checkpoint. A kinome shRNA screen revealed that carboplatin-resistant cells are vulnerable to the depletion of the mitotic checkpoint regulators, whereas the checkpoint kinases CHEK1 and WEE1 are indispensable for the survival of carboplatin-resistant cells in the presence of carboplatin. We confirmed that pharmacological inhibition of CHEK1 by prexasertib in the presence of carboplatin is well tolerated by mice and suppresses the growth of carboplatin-resistant TNBC xenografts. Thus, abrogation of the mitotic checkpoint by CHEK1 inhibition re-sensitizes carboplatin-resistant TNBCs to carboplatin and represents a potential strategy for the treatment of carboplatin-resistant TNBCs. [ABSTRACT FROM AUTHOR]

Appropriate drainage duration is vital for the postoperative rehabilitation of patients with breast cancer (BC) undergoing modified radical mastectomy (MRM). To provide better and individualized postoperative management for these patients, this study explored independent predictors of postoperative drainage duration in patients with BC. This was a single-center retrospective cohort study. Patients diagnosed with BC and treated with MRM from May 2016 to April 2020 were randomly divided into training (n = 729) and validation (n = 243) cohorts. Univariate and multivariate Cox analyses revealed that the body mass index, serum albumin level, hypertension, number of total dissected axillary lymph nodes, and ratio of positive axillary lymph nodes were independent predictors of postoperative drainage duration in the training cohort. Based on independent predictors, a nomogram was constructed to predict the median postoperative drainage duration and the probability of retaining the suction drain during this period. This nomogram had good concordance and discrimination both in the training and validation cohorts and could effectively predict the probability of retaining the suction drain during drainage, thus assisting clinicians in predicting postoperative drainage duration and providing individualized postoperative management for patients with BC. [ABSTRACT FROM AUTHOR]

The present study aimed to investigate the efficacy and toxicity of pegylated liposomal doxorubicin (PLD) in preoperative neoadjuvant chemotherapy for patients with breast cancer by comparing with conventional anthracycline. This study is a non-randomized controlled trial. Prospective analysis was conducted after matching as required. A total of 146 patients with confirmed diagnosis of breast cancer by histopathological examinations were enrolled into the observation group and control group in 1:1 ratio. Each of the cases in the observation group was required to correspond to another in the control group according to the requirements including age, molecular subtype, axillary node status, and regimen of the preoperative neoadjuvant chemotherapy. The chemotherapy was based on regimens consisting of anthracyclines, paclitaxel or docetaxel, and/or platinum. PLD was used at least twice in the observation group, with traditional anthracycline as a contrast in the control group. Clinical responses as well as cardiac side effects and other adverse reactions were evaluated by clinical and imaging examinations such as electrocardiogram (ECG) and color Doppler ultrasound during the chemotherapy. Pathologic examinations were performed following the surgeries after preoperative neoadjuvant chemotherapy. All the patients in both groups completed the preoperative neoadjuvant chemotherapy according to their original regimens. The postoperative pathological evaluation revealed a higher pathologic complete response (PCR) rate and significantly more patients of grade V of the Miller-Payne grading system in the observation group as compared to the control group (p = 0.047). In addition, the observation group recorded an evidently lower occurrence of the adverse cardiac events (p = 0.014), ECG changes (p = 0.048), and the relatively severe adverse reactions such as myelosuppression. Compared with conventional anthracycline drugs, PLD has a better pathologic response and safety performance, as well as a similar clinical effectiveness in preoperative neoadjuvant chemotherapy for breast cancer. [ABSTRACT FROM AUTHOR]

Extensive clinical trials indicate that patients with negative sentinel lymph node biopsy do not need axillary lymph node dissection (ALND). However, the ACOSOG Z0011 trial indicates that patients with clinically negative axillary lymph nodes (ALNs) and 1–2 positive sentinel lymph nodes having breast conserving surgery with whole breast radiotherapy do not benefit from ALND. The aim of this study is therefore to identify those patients with 0–2 positive nodes who might avoid ALND. A total of 486 patients were eligible for the study with 212 patients in the modeling group and 274 patients in the validation group, respectively. Clinical lymph node status, histologic grade, estrogen receptor status, and human epidermal growth factor receptor 2 status were found to be significantly associated with ALN metastasis. A negative binomial regression (NBR) model was developed to predict the probability of having 0–2 ALN metastases with the area under the curve of 0.881 (95% confidence interval 0.829–0.921, P < 0.001) in the modeling group and 0.758 (95% confidence interval 0.702–0.807, P < 0.001) in the validation group. Decision curve analysis demonstrated that the model was clinically useful. The NBR model demonstrated adequate discriminative ability and clinical utility for predicting 0–2 ALN metastases. [ABSTRACT FROM AUTHOR]

Tamoxifen resistance is emerging as a big challenge in endocrine therapy of luminal A breast cancer patients. In this study, we aimed to determine the molecular changes of PI3K/AKT/PTEN signaling pathway during tamoxifen-resistance development using gradually increased doses of tamoxifen in one model, while fixing tamoxifen treatment dose at 35 μM for several times in the second model. An upregulation of AKT/PI3K genes was noticed at 30 μM tamoxifen concentration in cells treated with a gradual increase of tamoxifen doses. In the second model, significant upregulation of AKT1 was seen in cells treated with 35 μM tamoxifen for three times. All genes studied showed a significant increase in expression in resistant cells treated with 50 µM and 35 µM six times tamoxifen. These genes' upregulation was accompanied by PTEN and GSK3 ß genes' down-regulation, and it was in correlation to the changes in the metabolic rate of glucose in tamoxifen-resistant models. A significant increase in glucose consumption rate from culture media was observed in tamoxifen resistant cells with the highest consumption rate reported in the first day of culturing. Increased glucose consumption rates were also correlated with GLUL significant gene expression and non-significant change in c-MYC gene expression that may lead to increased endogenous glutamine synthesis. As a result, several molecular and metabolic changes precede acquired tamoxifen resistance could be used as resistance biomarkers or targets to reverse tamoxifen resistance. [ABSTRACT FROM AUTHOR]

Polymeric nanoparticles (NPs) are commonly used as nanocarriers for drug delivery, whereby their sizes can be altered for a more efficient delivery of therapeutic active agents with better efficacy. In this work, cross-linked copolymers acted as core–shell NPs from acrylated palm olein (APO) with polyol ester were synthesized via gamma radiation-induced reversible addition-fragmentation chain transfer (RAFT) polymerisation. The particle diameter of the copolymerised poly(APO-b-polyol ester) core–shell NPs was found to be less than 300 nm, have a low molecular weight (MW) of around 24 kDa, and showed a controlled MW distribution of a narrow polydispersity index (PDI) of 1.01. These properties were particularly crucial for further use in designing targeted NPs, with inclusion of peptide for the targeted delivery of paclitaxel. Moreover, the characterisation of the synthesised NPs using Fourier Transform-Infrared (FTIR) and Neutron Magnetic Resonance (NMR) analyses confirmed the possession of biodegradable hydrolysed ester in its chemical structures. Therefore, it can be concluded that the synthesised NPs produced may potentially contribute to better development of a nano-structured drug delivery system for breast cancer therapy. [ABSTRACT FROM AUTHOR]

The aims of this study were to investigate the impact of the relative dose intensity (RDI) of chemotherapy on disease-free survival (DFS) and overall survival (OS), to identify the optimal RDI cut-off points with the docetaxel, epirubicin and cyclophosphamide (TEC) regimen for stage I–III breast cancer patients and to explore the adverse events in these patients. To achieve this, we performed a retrospective analysis of breast cancer patients treated at the First Affiliated Hospital of Chongqing Medical University in 2011. The results showed that among 293 patients with the TEC regimen, 85% and 80% were the cut-off points at which a high RDI was associated with better overall survival (HR = 2.04; 95% CI 1.13, 3.70; p = 0.02) and disease-free survival (HR = 1.97; 95% CI 1.14–3.42; p = 0.02), respectively. Among 169 HR(+) patients, 80% was the cut-off point for DFS (HR = 2.33; 95% CI 1.07–5.08; p = 0.03), and 85% was the cut-off point for OS (HR = 3.00; 95% CI 1.24–7.26; p = 0.02). Among 105 HR(−) patients, 80% was the cut-off point for OS (HR = 2.86; 95% CI 1.05–7.80; p = 0.04). Of 293 patients, neutropenia, nausea, and vomiting were found to be correlated with the level of RDI. In conclusion, a higher RDI of chemotherapy is associated with better survival but with a higher probability of causing adverse events. To optimize survival benefits, the RDI should be maintained ≥ 85% for HR(+) patients and ≥ 80% for HR(−) patients. [ABSTRACT FROM AUTHOR]

Taxane-based chemotherapy is frequently used in neoadjuvant treatment of breast cancer patients to reduce tumor growth and lymph node metastasis. However, few patients benefit from chemotherapy and predictive biomarkers of chemoresistance are needed. The microtubule-associated protein ATIP3 has recently been identified as a predictive biomarker whose low levels in breast tumors are associated with increased sensitivity to chemotherapy. In this study, we investigated whether ATIP3 deficiency may impact the effects of paclitaxel on cancer cell migration and lymph node metastasis. Expression levels of ATIP3 were analyzed in a cohort of 133 breast cancer patients and classified according to lymph node positivity following neoadjuvant chemotherapy. Results showed that low ATIP3 levels are associated with reduced axillary lymph node metastasis. At the functional level, ATIP3 depletion increases cell migration, front-rear polarity and microtubule dynamics at the plus ends, but paradoxically sensitizes cancer cells to the inhibitory effects of paclitaxel on these processes. ATIP3 silencing concomitantly increases the incorporation of fluorescent derivative of Taxol along the microtubule lattice. Together our results support a model in which alterations of microtubule plus ends dynamics in ATIP3-deficient cells may favor intracellular accumulation of paclitaxel, thereby accounting for increased breast tumor sensitivity to chemotherapy. [ABSTRACT FROM AUTHOR]

Metastatic breast cancer dominates the female cancer-related mortality. Tumour-associated molecules represents a crucial for early disease detection and identification of novel therapeutic targets. Nanomaterial technologies provide promising novel approaches to disease diagnostics and therapeutics. In the present study we extend the investigations of antitumoral properties of Carbon Dots prepared from N-hydroxyphthalimide (CD-NHF) precursor. We evaluate the effect of CD-NHF on tumour cell migration and invasion in vitro and their impact on tumour progression using an in vivo model. Furthermore, we investigate the molecular mechanisms involved in CD-NHF antitumour effects. In vivo mammary tumours were induced in Balb/c female mice by injecting 4T1 cells into the mammary fat pad. Conditional treatment with CD-NHF significantly impair both migration and invasion of metastatic breast cancer cells. The presence of CD-NHF within the 3D cell cultures strongly inhibited the malignant phenotype of MDA-MB-231, 4T1 and MCF-7 cells in 3D culture, resulting in culture colonies lacking invasive projections and reduction of mammospheres formation. Importantly, breast tumour growth and metastasis dissemination was significantly reduced upon CD-NHF treatments in a syngeneic mouse model and is associated with down-regulation of Ki67 and HSP90 expression. CD-NHF nanostructures provide exciting perspective for improving treatment outcome in breast cancer. [ABSTRACT FROM AUTHOR]

Cleavage factor "CFIm25", as a key repressor at proximal poly (A) site, negatively correlates to cell proliferation and tumorigenicity in various cancers. Hence, understanding CFIm25 mechanism of action in breast cancer would be a great benefit. To this aim four steps were designed. First, potential miRNAs that target 3′-UTR of CFIm25 mRNA, retrieved from Targetscan web server. Second, screened miRNAs were profiled in 100 breast cancer and 100 normal adjacent samples. Third, miRNAs that their expression was inversely correlated to the CFIm25, overexpressed in MDA-MB-231 cell line, and their effect on proliferation and migration monitored via MTT and wound healing assays, respectively. Fourth, interaction of miRNAs of interest with 3′-UTR of CFIm25 confirmed via luciferase assay and western blot. Our results indicate that CFIm25 considerably down-regulates in human breast cancer tissue. qRT-PCR assay, luciferase test, and western blotting confirm that CFIm25 itself could be directly regulated by oncomiRs such as miR-23, -24, -27, -135, -182 and -374. Besides, according to MTT and wound healing assays of cell lines, CFIm25 knockdown intensifies cell growth, proliferation and migration. Our results also confirm indirect impact of CFIm25 on regulation of mRNA's 3′–UTR length, which then control corresponding miRNAs' action. miRNAs directly control CFIm25 expression level, which then tunes expression of the oncogenes and tumor proliferation. Therefore, regulation of CFIm25 expression level via miRNAs is expected to improve treatment responses in breast cancer. [ABSTRACT FROM AUTHOR]

The use of postmastectomy radiation therapy (PMRT) has been recommended for patients with 4 or more positive lymph nodes, however, its role in patients with 1-3 positive lymph nodes remains unclear. The purpose of this study is to evaluate oncological outcomes for breast cancer patients with T1-2 tumors and 1-3 positive lymph nodes after undergoing PMRT. We performed a single-institution retrospective investigation that evaluated the association between PMRT and outcomes in breast cancer patients with T1-2 tumors and 1-3 positive lymph nodes, who underwent mastectomy from 2004 to 2015. Multivariable Cox proportional hazards regression was used to evaluate the association of PMRT with disease-free survival and overall survival. A total of 379 patients met inclusion criteria, of which 204 (54%) received PMRT while 175 (46%) did not receive PMRT following mastectomy and were followed over a median of 5.2 years (25th–75th percentile: 2.8–8.4 years). Recurrence was similar in patients receiving PMRT compared to those that did not: locoregional (0 vs 3, P = 0.061), distant (9 vs 3, P = 0.135) and any recurrence (11 vs 7, P = 0.525). After adjustment for potential confounding variables, PMRT was not associated with a statistically significant difference in disease-free survival (HR: 0.93; 95% CI: 0.48, 1.79) or overall survival (HR: 0.91; 95% CI: 0.45, 1.85). PMRT was not associated with improved oncological outcomes in patients with T1-2 breast cancer and 1-3 positive lymph nodes at our institution. [ABSTRACT FROM AUTHOR]

Subsets of breast tumors present major clinical challenges, including triple-negative, metastatic/recurrent disease and rare histologies. Here, we developed 37 patient-derived xenografts (PDX) from these difficult-to-treat cancers to interrogate their molecular composition and functional biology. Whole-genome and transcriptome sequencing and reverse-phase protein arrays revealed that PDXs conserve the molecular landscape of their corresponding patient tumors. Metastatic potential varied between PDXs, where low-penetrance lung micrometastases were most common, though a subset of models displayed high rates of dissemination in organotropic or diffuse patterns consistent with what was observed clinically. Chemosensitivity profiling was performed in vivo with standard-of-care agents, where multi-drug chemoresistance was retained upon xenotransplantation. Consolidating chemogenomic data identified actionable features in the majority of PDXs, and marked regressions were observed in a subset that was evaluated in vivo. Together, this clinically-annotated PDX library with comprehensive molecular and phenotypic profiling serves as a resource for preclinical studies on difficult-to-treat breast tumors. Savage et al. employ whole-genome, transcriptome sequencing and reverse-phase protein arrays on 37 developed breast cancer patient-derived xenografts (PDX) models to identify potential therapeutic targets, metastatic potential and chemosensitivity. This PDX library with comprehensive molecular and phenotypic profiling could serve as a resource for preclinical studies on difficult-to-treat breast tumors. [ABSTRACT FROM AUTHOR]

As one of the main components of Tripterygium wilfordii Hook F, celastrol (CSL) has significant antitumor activity, but its clinical application has been limited by its poor solubility, low oral bioavailability and systemic toxicity. In this study, celastrol nanosuspensions (CSL-NSps) were prepared using an antisolvent precipitation method with poloxamer 188 (P-188) as a stabilizer at a high CSL/P-188 feeding ratio of 8:1. The resultant CSL was spherical in shape with an average particle size of 147.9 nm, a polydispersity index (PDI) of 0.12 and zeta potential of -19.2 mV. The encapsulation efficiency and drug loading content were 98.18% and 86.83%, respectively, and the X-ray diffraction (XRD) pattern showed that CSL existed in an amorphous state in the nanosuspensions. CSL-NSps were quite stable in various physiological media and plasma and were both suitable for oral and intravenous administration. Nanosuspensions greatly enhanced the in vitro dissolution, and the cumulative drug release reached approximately 69.20% within 48 h. In vivo, CSL-NSps (3 mg/kg, i.g.) displayed a significantly enhanced tumor inhibition rate (TIR) in comparison with that of CSL suspension when administered orally (TIR, 50.39%, vs. 41.16%, p < 0.05), similar to that of PTX injection (8 mg/kg, i.v. TIR, 50.88%). CSL-NSps showed even better therapeutic efficacy than PTX injection (TIR, 64.18%, p < 0.01) when intravenously injected. This has demonstrated that, with the help of nanosuspensions, CSL is likely to be an effective and promising antitumor agent in clinic practice for the treatment of breast cancer. [ABSTRACT FROM AUTHOR]

Propofol, a common intravenous anesthetic, has been found to exert anti-cancer effects with inhibition of cancer cell proliferation, migration and invasion. We tested its possible action against HER2-overexpressing breast cancer cells that developed resistance against trastuzumab. Cell viability assay, ELISA for cytokines, mammosphere formation, quantitative RT-PCR for EMT/IL-6-targeting miRNAs and the in vivo experimental pulmonary metastasis model were performed to understand the epigenetic action of propofol. Propofol sensitized HER2 overexpressing cells to trastuzumab but such action was even more pronounced in resistant cells. Increased cytokines IL-6 as well as IL-8 were released by resistant cells, along with increased mammospheres and induction of EMT, all of which was inhibited by propofol. IL-6 targeting tumor suppressor miR-149-5p was found to be the novel miRNA that was up-regulated by propofol, resulting in the observed effects on cell viability, IL-6 production, mammospheres generation as well as EMT induction. Further, antagonizing miR-149-5p attenuated the propofol effects confirming the epigenetic activity of propofol through miR-149-5p regulation. Finally, in vivo validation in an experimental metastasis model conformed an inhibitory action of propofol against experimental lung metastasis and the essential mechanistic role of miR-149-5p/IL-6 loop. These results present a novel role of general anesthetic propofol against resistant breast cancer cells and the underlying epigenetic regulation of a tumor suppressor miRNA. [ABSTRACT FROM AUTHOR]

Here we investigated the roles of Rab27a, a player in exosome release, and TRAF3IP2, an inflammatory mediator, in development and metastasis of breast cancer (BC) in vivo. Knockdown (KD) of Rab27a (MDAKDRab27a) or TRAF3IP2 (MDAKDTRAF3IP2) in triple negative MDA-MB231 cells reduced tumor growth by 70–97% compared to wild-type tumors (MDAw). While metastasis was detected in MDAw-injected animals, none was detected in MDAKDRab27a- or MDAKDTRAF3IP2-injected animals. Interestingly, micrometastasis was detected only in the MDAKDRab27a-injected group. In addition to inhibiting tumor growth and metastasis, silencing TRAF3IP2 disrupted inter-cellular inflammatory mediator-mediated communication with mesenchymal stem cells (MSCs) injected into contralateral mammary gland, evidenced by the lack of tumor growth at MSC-injected site. Of translational significance, treatment of pre-formed MDAw-tumors with a lentiviral-TRAF3IP2-shRNA not only regressed their size, but also prevented metastasis. These results demonstrate that while silencing Rab27a and TRAF3IP2 each inhibited tumor growth and metastasis, silencing TRAF3IP2 is more effective; targeting TRAF3IP2 inhibited tumor formation, regressed preformed tumors, and prevented both macro- and micrometastasis. Silencing TRAF3IP2 also blocked interaction between tumor cells and MSCs injected into the contralateral gland, as evidenced by the lack of tumor formation on MSCs injected site. These results identify TRAF3IP2 as a novel therapeutic target in BC. [ABSTRACT FROM AUTHOR]

Breast cancer (BC) is a heterogeneous disease where genomic alterations, protein expression deregulation, signaling pathway alterations, hormone disruption, ethnicity and environmental determinants are involved. Due to the complexity of BC, the prediction of proteins involved in this disease is a trending topic in drug design. This work is proposing accurate prediction classifier for BC proteins using six sets of protein sequence descriptors and 13 machine-learning methods. After using a univariate feature selection for the mix of five descriptor families, the best classifier was obtained using multilayer perceptron method (artificial neural network) and 300 features. The performance of the model is demonstrated by the area under the receiver operating characteristics (AUROC) of 0.980 ± 0.0037, and accuracy of 0.936 ± 0.0056 (3-fold cross-validation). Regarding the prediction of 4,504 cancer-associated proteins using this model, the best ranked cancer immunotherapy proteins related to BC were RPS27, SUPT4H1, CLPSL2, POLR2K, RPL38, AKT3, CDK3, RPS20, RASL11A and UBTD1; the best ranked metastasis driver proteins related to BC were S100A9, DDA1, TXN, PRNP, RPS27, S100A14, S100A7, MAPK1, AGR3 and NDUFA13; and the best ranked RNA-binding proteins related to BC were S100A9, TXN, RPS27L, RPS27, RPS27A, RPL38, MRPL54, PPAN, RPS20 and CSRP1. This powerful model predicts several BC-related proteins that should be deeply studied to find new biomarkers and better therapeutic targets. Scripts can be downloaded at https://github.com/muntisa/neural-networks-for-breast-cancer-proteins. [ABSTRACT FROM AUTHOR]

Humanin (HN) is a mitochondrial-derived peptide with cytoprotective effect in many tissues. Administration of HN analogs has been proposed as therapeutic approach for degenerative diseases. Although HN has been shown to protect normal tissues from chemotherapy, its role in tumor pathogenesis is poorly understood. Here, we evaluated the effect of HN on the progression of experimental triple negative breast cancer (TNBC). The meta-analysis of transcriptomic data from The Cancer Genome Atlas indicated that HN and its receptors are expressed in breast cancer specimens. By immunohistochemistry we observed up-regulation of HN in TNBC biopsies when compared to mammary gland sections from healthy donors. Addition of exogenous HN protected TNBC cells from apoptotic stimuli whereas shRNA-mediated HN silencing reduced their viability and enhanced their chemo-sensitivity. Systemic administration of HN in TNBC-bearing mice reduced tumor apoptotic rate, impaired the antitumor and anti-metastatic effect of chemotherapy and stimulated tumor progression, accelerating tumor growth and development of spontaneous lung metastases. These findings suggest that HN may exert pro-tumoral effects and thus, caution should be taken when using exogenous HN to treat degenerative diseases. In addition, our study suggests that HN blockade could constitute a therapeutic strategy to improve the efficacy of chemotherapy in breast cancer. [ABSTRACT FROM AUTHOR]