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In the medical field, it is delicate to anticipate good performance in using deep learning due to the lack of large-scale training data and class imbalance. In particular, ultrasound, which is a key breast cancer diagnosis method, is delicate to diagnose accurately as the quality and interpretation of images can vary depending on the operator's experience and proficiency. Therefore, computer-aided diagnosis technology can facilitate diagnosis by visualizing abnormal information such as tumors and masses in ultrasound images. In this study, we implemented deep learning-based anomaly detection methods for breast ultrasound images and validated their effectiveness in detecting abnormal regions. Herein, we specifically compared the sliced-Wasserstein autoencoder with two representative unsupervised learning models autoencoder and variational autoencoder. The anomalous region detection performance is estimated with the normal region labels. Our experimental results showed that the sliced-Wasserstein autoencoder model outperformed the anomaly detection performance of others. However, anomaly detection using the reconstruction-based approach may not be effective because of the occurrence of numerous false-positive values. In the following studies, reducing these false positives becomes an important challenge. [ABSTRACT FROM AUTHOR]

The surgical range of breast cancer that shows pathologic complete response (pCR) without change in microcalcifications after neoadjuvant chemotherapy (NAC) is controversial. This study examined whole breast specimens to evaluate the necessity of mastectomy in those cases. The viability of cancer cells around the residual microcalcification was assessed using prospectively collected breast samples to confirm the presence or absence of cancer cells. A total of 144 patients with breast cancer and diffuse microcalcifications were classified into the reduced mass with no change in residual microcalcification (RESMIN, n = 49) and non-RESMIN (n = 95) groups. Five specimens were prospectively evaluated to assess the presence of viable cancer cells around the microcalcification. Tumor responses to NAC were significantly better with high pCR rates in the RESMIN group (p = 0.005 and p = 0.002). The incidence of human epidermal growth factor receptor 2-positive and triple-negative breast cancers was significantly high in the RESMIN group (p = 0.007). Although five (10.2%) patients had locoregional recurrence in the RESMIN group, no local recurrence in the breast was reported. Although pCR was highly estimated, residual cancers, including ductal carcinoma in situ, remained in 80% cases. Therefore, given the weak scientific evidence available currently, complete removal of residual microcalcifications should be considered for oncologic safety. [ABSTRACT FROM AUTHOR]

PARP inhibitors (PARPi) have drastically changed the treatment landscape of advanced ovarian tumors with BRCA mutations. However, the impact of this class of inhibitors in patients with advanced BRCA-mutant breast cancer is relatively modest. Using a syngeneic genetically-engineered mouse model of breast tumor driven by Brca1 deficiency, we show that tumor-associated macrophages (TAMs) blunt PARPi efficacy both in vivo and in vitro. Mechanistically, BRCA1-deficient breast tumor cells induce pro-tumor polarization of TAMs, which in turn suppress PARPi-elicited DNA damage in tumor cells, leading to reduced production of dsDNA fragments and synthetic lethality, hence impairing STING-dependent anti-tumor immunity. STING agonists reprogram M2-like pro-tumor macrophages into an M1-like anti-tumor state in a macrophage STING-dependent manner. Systemic administration of a STING agonist breaches multiple layers of tumor cell-mediated suppression of immune cells, and synergizes with PARPi to suppress tumor growth. The therapeutic benefits of this combination require host STING and are mediated by a type I IFN response and CD8+ T cells, but do not rely on tumor cell-intrinsic STING. Our data illustrate the importance of targeting innate immune suppression to facilitate PARPi-mediated engagement of anti-tumor immunity in breast cancer. PARP inhibitor (PARPi) therapy has demonstrated only modest efficacy in advanced breast cancer with BRCA mutations. Here the authors show that, by suppressing PARPi-triggered DNA damage and reducing dsDNA production in BRCA1-deficient breast tumor cells, tumor associated macrophages contribute to PARPi resistance, that can be overcome by STING agonism. [ABSTRACT FROM AUTHOR]

Peritumoral edema (PE) of breast cancer at T2-weighted MR images is considered a poor prognostic sign and may represent the microenvironment surrounding the tumor; however, its histopathological mechanism remains unclear. The purpose of the study was to identify and describe detailed histopathological characteristics associated with PE at preoperative breast MRI in breast cancer patients. This retrospective study included breast cancer patients who had undergone preoperative MRI and surgery between January 2011 and December 2012. Two radiologists determined the presence of PE in consensus based on the signal intensity surrounding the tumor at T2-weighted images. The following detailed histopathological characteristics were reviewed by two breast pathologists using four-tiered grades; lymphovascular invasion, vessel ectasia, stromal fibrosis, growth pattern, and tumor budding. Tumor necrosis and tumor infiltrating lymphocytes were assessed using a percent scale. Baseline clinicopathological characteristics, including age and histologic grade, were collected. The associations between detailed histopathologic characteristics and PE were examined using multivariable logistic regression with odds ratio (OR) calculation. A total of 136 women (median age, 49 ± 9 years) were assessed; among them 34 (25.0%) had PE. After adjustment of baseline clinicopathological characteristics that were significantly associated with PE (age, T stage, N stage, histologic grade, and subtype, all Ps < 0.05), lymphovascular invasion (P = 0.009), vessel ectasia (P = 0.021), stromal fibrosis (P = 0.024), growth pattern (P = 0.036), and tumor necrosis (P < 0.001) were also associated with PE. In comparison with patients without PE, patients with PE were more likely to have a higher degree of lymphovascular invasion (OR, 2.9), vessel ectasia (OR, 3.3), stromal fibrosis (OR, 2.5), lesser degree of infiltrative growth pattern (OR, 0.4), and higher portion of tumor necrosis (OR, 1.4). PE of breast cancer at MRI is associated with detailed histopathological characteristics of lymphovascular invasion, vessel ectasia, stromal fibrosis, growth pattern, and tumor necrosis, suggesting a relevance for tumor microenvironment. [ABSTRACT FROM AUTHOR]

Our previous study found that highly metastatic breast cancer cells, such as MDA-MB-231 cells, release higher levels of ATP and exhibit greater P2Y2 receptor (P2Y2R) activity than lowly metastatic breast cancer cells, and that P2Y2R activation mediated by ATP plays a significant role in tumor progression and metastasis. In addition, we reported that radiotherapy-resistant (RT-R) breast cancer cells promote invasion and tumor growth through the activation of P2Y2R by ATP released from RT-R-breast cancer cells than breast cancer cells. Moreover, increased numbers of cancer stem cells (CSCs) were observed among the RT-R-breast cancer cell population. Therefore, in this study, we investigated the expression level of five CSC markers (CD24, CD44, Oct3/4, Notch-4 and ALDH1A1) as well as P2Y2R in the tumor tissues of patients with breast cancer and determined which CSC marker correlates with P2Y2R in breast cancer. According to the immunohistochemical analysis, CD44, Oct3/4 and Notch-4 but not ALDH1A1 were significantly expressed in the tumor tissues (n=180) compared with the normal epithelial tissues (n=20) of patients with breast cancer. It was demonstrated that P2Y2R expression was increased in tumor tissues of patients with breast cancer compared with normal epithelial tissue. Notably, it was identified that P2Y2R expression has a significant correlation with only the CSC marker Notch-4 in patients with breast cancer. The results of this study suggested for the first time to the best of our knowledge that Notch-4 has a notable correlation with P2Y2R, which has important roles in tumor progression and metastasis. [ABSTRACT FROM AUTHOR]

The goal of this study was to evaluate various clinicopathologic and imaging characteristics as independent predictors of axillary pathologic complete response (pCR) to neoadjuvant chemotherapy (NAC) and to determine the added value of a model that integrates imaging characteristics of ultrasound (US) restaging with known clinicopathologic characteristics. A total of 227 clinically node-positive breast cancer patients underwent axillary US after NAC (termed US restaging) before surgery. We constructed a clinicopathologic model with independent predictors of clinicopathologic characteristics in multivariate analyses. A combined model was created by integrating imaging characteristics with clinicopathologic characteristics. The predictive values of the models were compared using the area under the receiver operating characteristic curve. Of the 227 patients, 106 (46.7%) achieved axillary pCR. Multivariate analysis revealed that higher histologic grades (odds ratio [OR] = 4.21 and 10.11 for moderate and high grade, respectively), negative hormonal receptor status (OR = 2.88), smaller (≤1.5 cm) residual tumor size (OR = 2.83), absence of fatty hilum loss (OR = 14.06) and absence of eccentric cortical thickening of the axillary lymph node (OR = 4.42) were independently associated with the axillary pCR (all p values < 0.05). Integrating the imaging characteristics of the US restaging significantly increased the predictive capability of the model that applied only the clinicopathologic characteristics (c-index, 0.783 vs. 0.657; p < 0.001). Imaging characteristics of the US restaging were independently associated with axillary pCR after NAC and they significantly improved the predictive capability of the model that used only the clinicopathologic characteristics. [ABSTRACT FROM AUTHOR]

Ultrasonography-guided fine-needle aspiration (US-guided FNA) for axillary lymph nodes (ALNs) is currently used with various techniques for the initial staging of breast cancer and tagging of ALNs. With the implementation of the tattooing of biopsied ALNs, the rate of false-negative results of US-guided FNA for non-palpable and suspicious ALNs and concordance with sentinel lymph nodes were determined by node-to node analyses. A total of 61 patients with breast cancer had negative results for metastasis on US-guided FNA of their non-palpable and suspicious ALNs. The biopsied ALNs were tattooed with an injection of 1-3 mL Charcotrace (Phebra, Lane Cove West, Australia) ink and removed during sentinel lymph node biopsy or axillary dissection. We determined the rate of false-negative results and concordance with the sentinel lymph nodes by a retrospective review of surgical and pathologic findings. The association of false-negative results with clinical and imaging factors was evaluated using logistic regression. Of the 61 ALNs with negative results for US-guided FNA, 13 (21%) had metastases on final pathology. In 56 of 61 ALNs (92%), tattooed ALNs corresponded to the sentinel lymph nodes. Among the 5 patients (8%) without correspondence, 1 patient (2%) had 2 metastatic ALNs of 1 tattooed node and 1 sentinel lymph node. In multivariate analysis, atypical cells on FNA results (odds ratio = 20.7, p = 0.040) was independently associated with false-negative FNA results. False-negative ALNs after US-guided FNA occur at a rate of 21% and most of the tattooed ALNs showed concordance with sentinel lymph nodes. [ABSTRACT FROM AUTHOR]

Purpose: In node-negative disease, the presence of lymphovascular invasion (LVI) is reported to be an unfavorable prognostic factor. Thus, the aim of this study was to evaluate whether preoperative breast MRI features are associated with LVI in patients with node-negative invasive breast cancer by a propensity-matched analysis.Materials and Methods: Among 389 patients with node-negative invasive ductal breast cancer who had preoperative breast 3.0 Tesla MRI with precontrast T2-weighted fat-suppressed, pre- and dynamic postcontrast T1-weighted fat-suppressed sequences, 61 patients with LVI (LVI group) were matched with 183 patients without LVI (no LVI group) at a ratio of 1:3 in terms of age, histologic grade, tumor size, and hormone receptor status. Two radiologists reviewed the MRI features, following profiles of focal breast edema (peritumoral, prepectoral, subcutaneous), intratumoral T2 signal intensity, adjacent vessel sign, and increased ipsilateral whole-breast vascularity, in addition to 2013 Breast Imaging Reporting and Data System lexicon.Results: The presence of peritumoral edema (45.9% [28/61] versus 30.6% [56/183], P = 0.030) and adjacent vessel sign (82.0% [50/61] versus 68.3% [125/183], P = 0.041) was significantly associated with LVI. Prepectoral edema was also more frequently observed in the LVI group than in the no LVI group with borderline significance (26.2% [16/61] versus 15.3% [28/183], P = 0.055). In cases of nonmass enhancement, regional enhancement was more frequently found in the LVI group than in the no LVI group (60.0% [3/4] versus 5.9% [1/4], P = 0.042).Conclusion: Preoperative breast MRI features may be associated with LVI in patients with node-negative invasive breast cancer.Level Of Evidence: 3 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2017;46:1037-1044. [ABSTRACT FROM AUTHOR]

Background: Most ductal carcinoma in situ (DCIS) of the breast is asymptomatic and usually manifests as calcifications in screening mammography. On the other hand, little is known about ultrasonographic (US) features of asymptomatic DCIS, for US is rarely used for the diagnosis and evaluation of DCIS because of low sensitivity in detecting microcalcifications. Purpose: To evaluate US detection and characterization of DCIS in asymptomatic women and correlate these imaging findings with the histopathologic features. Material and Methods: This retrospective study evaluated mammographic and US images of 60 DCIS cases from 59 asymptomatic women. US was performed in knowledge of mammographic findings. The following histopathologic parameters were analyzed: Van Nuys classification, architectural pattern, and presence of microinvasion. Image detectability and US features were correlated with these histopathologic parameters. Results: Of the 54 cases (90.0%) detected on mammography, 48 cases (88.9%) had microcalcifications only, 5 (9.3%) had microcalcifications with associated density, and 1 (1.9%) had soft tissue density alone. Of the 38 cases (63.3%) identified by US, 29 cases (76.3%) had a mass with or without microcalcifications, six (15.8%) had microcalcifications only, and three (7.9%) had other findings. US identified lesions were associated with higher Van Nuys groups, microinvasion and comedocarcinoma (P = 0.044, P = 0.024, and P = 0.032, respectively). The most common US finding was a not-circumscribed, oval mass with parallel orientation and normal acoustic transmission. Microcalcifications were seen on US in 31 (81.6%) of the 38 US visible cases; this finding showed a trend of association with Van Nuys group 2 and 3 but was not statistically significant (P = 0.063). Conclusion: When DCIS was identified on US, it was associated with more aggressive histopathologic type. However, mammographic correlation is essential to differentiate benign from malignant lesion in cases seen by US; US findings of asymptomatic DCIS had a low suspicion of malignancy. [ABSTRACT FROM AUTHOR]

Emerging evidence suggests that breast cancer stem cells (BCSCs), and epithelial–mesenchymal transition (EMT) may be involved in resistance to doxorubicin. However, it is unlear whether the doxorubicin-induced EMT and expansion of BCSCs is related to cancer dormancy, or outgrowing cancer cells with maintaining resistance to doxorubicin, or whether the phenotypes can be transferred to other doxorubicin-sensitive cells. Here, we characterized the phenotype of doxorubicin-resistant TNBC cells while monitoring the EMT process and expansion of CSCs during the establishment of doxorubicin-resistant MDA-MB-231 human breast cancer cells (DRM cells). In addition, we assessed the potential signaling associated with the EMT process and expansion of CSCs in doxorubicin-resistance of DRM cells. DRM cells exhibited morphological changes from spindle-shaped MDA-MB-231 cells into round-shaped giant cells. They exhibited highly proliferative, EMT, adhesive, and invasive phenotypes. Molecularly, they showed up-regulation of Cyclin D1, mesenchymal markers (β-catenin, and N-cadherin), MMP-2, MMP-9, ICAM-1 and down-regulation of E-cadherin. As the molecular mechanisms responsible for the resistance to doxorubicin, up-regulation of EGFR and its downstream signaling, were suggested. AKT and ERK1/2 expression were also increased in DRM cells with the advancement of resistance to doxorubicin. Furthermore, doxorubicin resistance of DRM cells can be transferred by autocrine signaling. In conclusion, DRM cells harbored EMT features with CSC properties possessing increased proliferation, invasion, migration, and adhesion ability. The doxorubicin resistance, and doxorubicin-induced EMT and CSC properties of DRM cells, can be transferred to parental cells through autocrine signaling. Lastly, this feature of DRM cells might be associated with the up-regulation of EGFR. [ABSTRACT FROM AUTHOR]

Exosomes are the small vesicles that are secreted by different types of normal and tumour cells and can incorporate and transfer their cargo to the recipient cells. The main goal of the present work was to study the tumour exosomes' ability to accumulate the parent mutant DNA or RNA transcripts with their following transfer to the surrounding cells. The experiments were performed on the MCF7 breast cancer cells that are characterized by the unique coding mutation in the PIK3CA gene. Using two independent methods, Sanger sequencing and allele-specific real-time PCR, we revealed the presence of the fragments of the mutant DNA and RNA transcripts in the exosomes secreted by the MCF7 cells. Furthermore, we demonstrated the MCF7 exosomes' ability to incorporate into the heterologous MDA-MB-231 breast cancer cells supporting the possible transferring of the exosomal cargo into the recipient cells. Sanger sequencing of the DNA from MDA-MB-231 cells (originally bearing a wild type of PIK3CA) treated with MCF7 exosomes showed no detectable amount of mutant DNA or RNA; however, using allele-specific real-time PCR, we revealed a minor signal from amplification of a mutant allele, showing a slight increase of mutant DNA in the exosome-treated MDA-MB-231 cells. The results demonstrate the exosome-mediated secretion of the fragments of mutant DNA and mRNA by the cancer cells and the exosomes' ability to transfer their cargo into the heterologous cells. [ABSTRACT FROM AUTHOR]

Cancer stem cells (CSCs) exist in solid tumors and contribute to therapeutic resistance and disease recurrence. Previously, we reported that radiotherapy-resistant (RT-R)-MDA-MB-231 cells from highly metastatic MDA-MB-231 cells produced more CSCs than any other RT-R-breast cancer cells and showed therapeutic resistance and enhanced invasiveness. Hypoxia inducible factor-1α (HIF-1α) induced in the tumor microenvironment leads to the release of lysyl oxidase (LOX), which mediates collagen crosslinking at distant sites to facilitate environmental changes that allow cancer cells to easily metastasize. Therefore, in this study, we investigated whether RT-R-MDA-MB-231 cells induce greater HIF-1α expression, LOX secretion, and premetastatic niche formation than MDA-MB-231 cells do. RT-R-MDA-MB-231 cells increased HIF-1α expression and LOX secretion compared with MDA-MB-231 cells. Mice harboring RT-R-MDA-MB-231 cell xenografts showed enhanced tumor growth and higher expression of the CSC markers, CD44, Notch-4, and Oct3/4. In addition, mice injected with RT-R-MDA-MB-231 cells exhibited a higher level of HIF-1α in tumor tissue, increased secretion of LOX in plasma, higher induced levels of crosslinked collagen, and a higher population of CD11b+ BMDC recruitment around lung tissue, compared with those injected with MDA-MB-231 cells. These results suggest that RT-R-MDA-MB-231 cells contribute to tumor progression by enhancing premetastatic niche formation through the HIF-1α-LOX axis. [ABSTRACT FROM AUTHOR]

Background: Preoperative breast magnetic resonance imaging (MRI) provides more information than mammography and ultrasonography for determining the surgical plan for patients with breast cancer. This study aimed to determine whether breast MRI is more useful for patients with ductal carcinoma in situ (DCIS) lesions than for those with invasive ductal carcinoma (IDC).Methods: A total of 1113 patients with breast cancer underwent mammography, ultrasonography, and additional breast MRI before surgery. The patients were divided into 2 groups: DCIS (n = 199) and IDC (n = 914), and their clinicopathological characteristics and oncological outcomes were compared. Breast surgery was classified as follows: conventional breast-conserving surgery (Group 1), partial mastectomy with volume displacement (Group 2), partial mastectomy with volume replacement (Group 3), and total mastectomy with or without reconstruction (Group 4). The initial surgical plan (based on routine mammography and ultrasonography) and final surgical plan (after additional breast MRI) were compared between the 2 groups. The change in surgical plan was defined as group shifting between the initial and final surgical plans.Results: Changes (both increasing and decreasing) in surgical plans were more common in the DCIS group than in the IDC group (P <  0.001). These changes may be attributed to the increased extent of suspicious lesions on breast MRI, detection of additional daughter nodules, multifocality or multicentricity, and suspicious findings on mammography or ultrasonography but benign findings on breast MRI. Furthermore, the positive margin incidence in frozen biopsy was not different (P = 0.138).Conclusions: Preoperative breast MRI may provide more information for determining the surgical plan for patients with DCIS than for those with IDC. [ABSTRACT FROM AUTHOR]

Anthocyanins isolated from Vitis coignetiae Pulliat (Meoru in Korea) (AIMs) have various anti-cancer properties by inhibiting Akt and NF-κB which are involved in drug resistance. Cisplatin (CDDP) is one of the popular anti-cancer agents. Studies reported that MCF-7 human breast cancer cells have high resistance to CDDP compared to other breast cancer cell lines. In this study, we confirmed CDDP resistance of MCF-7 cells and tested whether AIMs can overcome CDDP resistance of MCF-7 cells. Cell viability assay revealed that MCF-7 cells were more resistant to CDDP treatment than MDA-MB-231 breast cancer cells exhibiting aggressive and high cancer stem cell phenotype. AIMs significantly augmented the efficacy of CDDP with synergistic effects on MCF-7 cells. Molecularly, Western blot analysis revealed that CDDP strongly increased Akt and moderately reduced p-NF-κB and p-IκB and that AIMs inhibited CDDP-induced Akt activation, and augmented CDDP-induced reduction of p-NF-κB and p-IκB in MCF-7 cells. In addition, AIMs significantly downregulated an anti-apoptotic protein, XIAP, and augmented PARP-1 cleavage in CDDP-treated MCF-7 cells. Moreover, under TNF-α treatment, AIMs augmented CDDP efficacy with inhibition of NF-κB activation on MCF-7 cells. In conclusion, AIMs enhanced CDDP sensitivity by inhibiting Akt and NF-κB activity of MCF-7 cells that show relative intrinsic CDDP resistance. [ABSTRACT FROM AUTHOR]

Vitis coignetiaePulliat (Meoru in Korea) has been used in Korean folk medicine for the treatment of inflammatory diseases and cancers. Evidence suggests that NF-κB activation is mainly involved in cancer cell proliferation, invasion, angiogenesis, and metastasis. TNF-α also enhances the inflammatory process in tumor development. Recently, flavonoids from plants have been reported to have inhibitory effects on NF-κB activities. We investigated the effects of anthocyanins extracted from the fruits of Vitis coignetiae Pulliat (AIM, anthocyanins isolated from Meoru (AIM)) on TNF-α-induced NF-κB activities in MCF-7 human breast cancer cells and the molecules involved in AIM-induced anti-cancer effects, especially on cancer metastasis. We performed cell viability assay, gelatin zymography, invasion assay, and western blot analysis to unravel the anti-NF-κB activity of AIMs on MCF-7 cells. AIM suppressed the TNF-α effects on the NF-κB-regulated proteins involved in cancer cell proliferation (COX-2, C-myc), invasion, and angiogenesis (MMP-2, MMP9, ICAM-1, and VEGF). AIM also increased the expression of E-cadherin, which is one of the hallmarks of the epithelial-mesenchymal transition (EMT) process. In conclusion, this study demonstrates that the anthocyanins isolated from the fruits of Vitis coignetiae Pulliat acts as an inhibitor of TNF-α induced NF-κB activation, and subsequent downstream molecules involved in cancer proliferation, invasion, adhesion, angiogenesis, and thus have anti-metastatic activities in MCF-7 breast cancer cells. [ABSTRACT FROM AUTHOR]

The inflammasomes are reported to be associated with tumor progression. In our previous study, we determined that extracellular ATP enhances invasion and tumor growth by inducing inflammasome activation in a P2Y purinergic receptor 2 (P2Y2R)-dependent manner. However, it is not clear which inflammasome among the diverse complexes is associated with P2Y2R activation in breast cancer. Thus, in this study, we determined which inflammasome components are regulated by P2Y2R activation and are involved in tumor progression in breast cancer cells and radiotherapy-resistant (RT-R)-breast cancer cells. First, we found that NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3); NLR family caspase activation and recruitment domain (CARD) containing 4 (NLRC4); apoptosis-associated speck-like protein containing a CARD complex (ASC); and caspase-1 mRNA levels were upregulated in RT-R-MDA-MB-231 cells compared to MDA-MB-231 cells, whereas tumor necrosis factor-α (TNF-α) or ATP treatment induced NLRC4, ASC, and caspase-1 but not NLRP3 protein levels. Moreover, TNF-α or ATP increased protein levels of NLRC4, ASC, and caspase-1 in a P2Y2R-dependent manner in MDA-MB-231 and RT-R-MDA-MB-231 cells. In addition, P2Y2R activation by ATP induced the secretion of IL-1β and VEGF-A, as well as invasion, in MDA-MB-231 and RT-R-MDA-MB-231 cells, which was inhibited by NLRC4, ASC, and caspase-1 small interfering RNA (siRNA). Taken together, this report suggests that P2Y2R activation by ATP induces tumor invasion and angiogenesis through inflammasome activation, specifically by regulating the inflammasome components NLRC4, ASC, and caspase-1. [ABSTRACT FROM AUTHOR]

Artemisia annua L. has been reported to show anti-cancer activities. Here, we determined whether polyphenols extracted from Artemisia annua L. (pKAL) exhibit anti-cancer effects on radio-resistant MDA-MB-231 human breast cancer cells (RT-R-MDA-MB-231 cells), and further explored their molecular mechanisms. Cell viability assay and colony-forming assay revealed that pKAL inhibited cell proliferation on both parental and RT-R-MDA-MB-231 cells in a dose-dependent manner. The anti-proliferative effects of pKAL on RT-R-MDA-MB-231 cells were superior or similar to those on parental ones. Western blot analysis revealed that expressions of cluster of differentiation 44 (CD44) and Oct 3/4, matrix metalloproteinase-9 (MMP-9) and signal transducer and activator of transcription-3 (STAT-3) phosphorylation were significantly increased in RT-R-MDA-MB-231 cells compared to parental ones, suggesting that these proteins could be associated with RT resistance. pKAL inhibited the expression of CD44 and Oct 3/4 (CSC markers), and β-catenin and MMP-9 as well as STAT-3 phosphorylation of RT-R-MDA-MB-231. Regarding upstream signaling, the JNK or JAK2 inhibitor could inhibit STAT-3 activation in RT-R-MDA-MB-231 cells, but not augmented pKAL-induced anti-cancer effects. These findings suggest that c-Jun N-terminal kinase (JNK) or Janus kinase 2 (JAK2)/STAT3 signaling are not closely related to the anti-cancer effects of pKAL. In conclusion, this study suggests that pKAL exhibit anti-cancer effects on RT-R-MDA-MB-231 cells by suppressing CD44 and Oct 3/4, β-catenin and MMP-9, which appeared to be linked to RT resistance of RT-R-MDA-MB-231 cells. [ABSTRACT FROM AUTHOR]

Background: We report on our experience of ultrasound (US)-guided dual-localization for axillary nodes before and after neoadjuvant chemotherapy (NAC) with clip and activated charcoal to guide axillary surgery in breast cancer patients.Methods: Between November 2017 and May 2018, a dual-localization procedure was performed under US guidance for the most suspicious axillary nodes noted at initial staging (before NAC, with clip) and restaging (after NAC, with activated charcoal) in 28 cytologically proven node-positive breast cancer patients. Patients underwent axillary sampling or dissection, which involved removing not only the sentinel nodes (SNs), but also clipped nodes (CNs) and tattooed nodes (TNs). Success (or failure) rates of biopsies of SNs, CNs, and TNs and inter-nodal concordance rates were determined. Sensitivities for the individual and combined biopsies were calculated.Results: SN biopsy failed in four patients (14%), whereas the CN biopsy failed in one patient (4%). All TNs were identified in the surgical field. Concordance rates were 79% for CNs-TNs, 63% for CNs-SNs, and 58% for TNs-SNs. Sensitivity for SN, CN, and TN biopsy was 73%, 67%, and 67%, respectively. Sensitivity was 80% for any combination of biopsies (SN plus CN, SN plus TN, SN plus CN plus TN).Conclusions: US-guided dual-localization of axillary nodes before and after NAC with clip and activated charcoal was a feasible approach that might facilitate more reliable nodal staging with less-invasive strategies in node-positive breast cancer patients. [ABSTRACT FROM AUTHOR]

Berberine is reported to have multiple biological effects, including antimicrobial, anti-inflammatory, and antitumor activities, and 13-alkyl-substituted berberines show higher activity than berberine against certain bacterial species and human cancer cell lines. In particular, 13-ethylberberine (13-EBR) was reported to have anti-inflammatory effects in endotoxin-activated macrophage and septic mouse models. Thus, in this study, we aimed to examine the anticancer effects of 13-EBR and its mechanisms in radiotherapy-resistant (RT-R) MDA-MB-231 cells derived from the highly metastatic MDA-MB-231 cells. When we compared the gene expression between MDA-MB-231 and RT-R MDA-MB-231 cells with an RNA microarray, RT-R MDA-MB-231 showed higher levels of anti-apoptotic genes and lower levels of pro-apoptotic genes compared to MDA-MB-231 cells. Accordingly, we examined the effect of 13-EBR on the induction of apoptosis in RT-R MDA-MB-231 and MDA-MB-231 cells. The results showed that 13-EBR reduced the proliferation and colony-forming ability of both MDA-MB-231 and RT-R MDA-MB-231 cells. Moreover, 13-EBR induced apoptosis by promoting both intracellular and mitochondrial reactive oxygen species (ROS) and by regulating the apoptosis-related proteins involved in the intrinsic pathway, not in the extrinsic pathway. These results suggest that 13-EBR has pro-apoptotic effects in RT-R MDA-MB-231 and MDA-MB-231 cells by inducing mitochondrial ROS production and activating the mitochondrial apoptotic pathway, providing useful insights into new potential therapeutic strategies for RT-R breast cancer treatment. [ABSTRACT FROM AUTHOR]

Depression is more common in women with breast cancer than the general population. Selective serotonin reuptake inhibitors (SSRIs), a group of antidepressants, are widely used for the treatment of patients with depression and a range of anxiety-related disorders. The association between the use of antidepressant medication and breast cancer is controversial. In this study, we investigated whether and how SSRIs induce the death of human breast cancer MCF-7 cells. Of the antidepressants tested in this study (amitriptyline, bupropion, fluoxetine, paroxetine, and tianeptine), paroxetine most reduced the viability of MCF-7 cells in a time-and dose-dependent manner. The exposure of MCF-7 cells to paroxetine resulted in mitochondrion-mediated apoptosis, which is assessed by increase in the number of cells with sub-G1 DNA content, caspase-8/9 activation, poly (ADP-ribose) polymerase cleavage, and Bax/Bcl-2 ratio and a reduction in the mitochondrial membrane potential. Paroxetine increased a generation of reactive oxygen species (ROS), intracellular Ca2+ levels, and p38 MAPK activation. The paroxetine-induced apoptotic events were reduced by ROS scavengers and p38 MAPK inhibitor, and the paroxetine's effect was dependent on extracellular Ca2+ level. Paroxetine also showed a synergistic effect on cell death induced by chemotherapeutic drugs in MCF-7 and MDA-MB-231 cells. Our results showed that paroxetine induced apoptosis of human breast cancer MCF-7 cells through extracellular Ca2+-and p38 MAPK-dependent ROS generation. These results suggest that paroxetine may serve as an anticancer adjuvant to current cancer therapies for breast cancer patients with or without depression. [ABSTRACT FROM AUTHOR]

Aims It has been reported that in human glioblastoma cells, phosphotase and tensin homolog (PTEN) positive cells are more prone to paclitaxel-induced apoptosis than PTEN-negative cells. We investigated whether (S)-1-(α-naphthylmethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (CKD712) enhances the therapeutic effects of paclitaxel (including effects on cellular proliferation, invasion and apoptosis) in MDA-MB-231 cells through PTEN and NF-κB activity. Main methods Cellular proliferation, invasion and apoptosis were assessed by MTT, Western blot analysis, and TUNEL assay. Key findings The combination of paclitaxel and CKD712 significantly decreased cell growth, invasion and MMP-9 expression/activity compared with paclitaxel alone. CKD712 enhanced the inhibition of cell growth and invasion in response to paclitaxel in scramble siRNA-transfected, but not siPTEN-transfected cells. CKD712 significantly increased the levels of apoptosis induced by paclitaxel and this apoptosis was accompanied by reduced expression of Bcl-xL but increased activation of caspase-3. TUNEL assay further confirms that CKD712 enhanced the apoptotic effect of paclitaxel. Interestingly, over-expression of PTEN decreased phosphorylation of IκBα and NF-κB expression in the nucleus, indicating that PTEN modifies NF-κB activity in MDA-MB-231 cells. CKD712 treatment also significantly reduced expression of p-IκB and NF-κB activity in TNF-α activated cells. Significance CKD712 strongly enhances the anti-cancer effects (proliferation, invasion, and apoptosis) of paclitaxel on MDA-MB-231 cells by regulating PTEN and NF-κB activity. [ABSTRACT FROM AUTHOR]