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Background: Though tamoxifen achieves success in treating estrogen receptor α (ERα)-positive breast cancer, the followed development of tamoxifen resistance is a common challenge in clinic. Signals downstream of prolactin receptor (PRLR) could synergize with ERα in breast cancer progression. However, the potential effect of targeting PRL-PRLR axis combined with tamoxifen has not been thoroughly investigated. Methods: High-throughput RNA-seq data obtained from TCGA, Metabric and GEO datasets were analyzed to explore PRLR expression in breast cancer cell and the association of PRLR expression with tamoxifen treatment. Exogenous or PRL overexpression cell models were employed to investigate the role of activated PRLR pathway in mediating tamoxifen insensitivity. Immunotoxin targeting PRLR (N8-PE24) was constructed with splicing-intein technique, and the efficacy of N8-PE24 against breast cancer was evaluated using in vitro and in vivo methods, including analysis of cells growth or apoptosis, 3D spheroids culture, and animal xenografts. Results: PRLR pathway activated by PRL could significantly decrease sensitivity of ERα-positive breast cancer cells to tamoxifen. Tamoxifen treatment upregulated transcription of PRLR and could induce significant accumulation of PRLR protein in breast cancer cells by alkalizing lysosomes. Meanwhile, tamoxifen-resistant MCF7 achieved by long-term tamoxifen pressure exhibited both upregulated transcription and protein level of PRLR. Immunotoxin N8-PE24 enhanced sensitivity of breast cancer cells to tamoxifen both in vitro and in vivo. In xenograft models, N8-PE24 significantly enhanced the efficacy of tamoxifen and paclitaxel when treating PRLR-positive triple-negative breast cancer. Conclusions: PRL-PRLR axis potentially associates with tamoxifen insensitivity in ERα-positive breast cancer cells. N8-PE24 could inhibit cell growth of the breast cancers and promote drug sensitivity of PRLR-positive breast cancer cells to tamoxifen and paclitaxel. Our study provides a new perspective for targeting PRLR to treat breast cancer. Highlights: Tamoxifen up-regulates PRLR protein level in breast cancer cells and activation of PRLR pathway by PRL could decrease drug-sensitivity of breast cancer cells to tamoxifen. The immunotoxin targeting PRLR could reverse drug-sensitivity to tamoxifen in tamoxifen-resistant breast cancer in vitro and in vivo. The immunotoxin targeting PRLR significantly improve the efficacy of chemotherapy in PRLR-positive TNBC and xenograft models. [ABSTRACT FROM AUTHOR]

Breast cancer is the leading cause of cancer-related deaths in the United States. The majority of deaths (90%) in breast cancer patients is caused by invasion and metastasis–two features related to the epithelial-to-mesenchymal transition (EMT). Twist1 is a key transcription factor that promotes the EMT, which leads to cell migration, invasion, cancer metastasis, and therapeutic resistance. Harmine is a beta-carboline alkaloid found in a variety of plants and was recently shown to be able to induce degradation of Twist Family BHLH Transcription Factor 1 (Twist1) in non-small cell lung cancer cells (NSCLC). In this study, we show that harmine can inhibit migration and invasion of both human and mouse breast cancer cells in a dose-dependent manner. Further study shows that this inhibition is most likely achieved by inducing a proteasome-dependent Twist1 degradation. At the concentrations tested, harmine did not affect the viability of cells significantly, suggesting that its inhibition of cancer cell migration and invasion is largely independent of its cytotoxicity, but due to its ability to affect regulators of EMT such as Twist1. This result may facilitate the development of strategies that target Twist1 to treat metastatic breast cancer, as Twist1 is expressed at a high level in metastatic breast cancer cells but not in normal cells. [ABSTRACT FROM AUTHOR]

Tamoxifen‐based hormone therapy is central for the treatment of estrogen receptor positive (ER+) breast cancer. However, the acquired tamoxifen resistance, typically co‐exists with hypoxia, remains a major challenge. We aimed to develop a non‐invasive, targeted ultrasound imaging approach to dynamically monitory of tamoxifen resistance. After we assessed acquired tamoxifen resistance in 235 breast cancer patients and a list of breast cancer cell lines, we developed poly(lactic‐co‐glycolic acid)‐poly(ethylene glycol)‐carbonic anhydrase IX mono antibody nanobubbles (PLGA‐PEG‐mAbCAIX NBs) to detect hypoxic breast cancer cells upon exposure of tamoxifen in nude mice. We demonstrate that carbonic anhydrase IX (CAIX) expression is associated with breast cancer local recurrence and tamoxifen resistance both in clinical and cellular models. We find that CAIX overexpression increases tamoxifen tolerance in MCF‐7 cells and predicts early tamoxifen resistance along with an oscillating pattern in intracellular ATP level in vitro. PLGA‐PEG‐mAbCAIX NBs are able to dynamically detect tamoxifen‐induced hypoxia and tamoxifen resistance in vivo. CAIX‐conjugated NBs with noninvasive ultrasound imaging is powerful for dynamically monitoring hypoxic microenvironment in ER+ breast cancer with tamoxifen resistance. [ABSTRACT FROM AUTHOR]

This study aimed to analyze the correlation between mammographic density obtained by density analysis software (DAS)/radiologists visual (RV) classification with molecular subtype, and the expression levels of estrogen receptor (ER), progesterone receptor (PR), Ki67 antigen (Ki-67), p53 gene (p53), and human epidermal growth factor receptor-2 (HER2). A total of 688 breast cancer patients with digital mammography and complete molecular pathological results in Tianjin Medical University Cancer Institute and Hospital between February 2015 and February 2016 were collected. The DAS-density grade (DASD) and the radiologists visually classified density grade (RVD) were evaluated by 3 radiologists. The correlation between density grade and the expression levels of ER, PR, Ki-67, p53, HER2 and breast cancer molecular subtype (PMS) were analyzed. The agreement between DASD and RVD was explored. ER, PR and HER-2 positive rate were significantly different among patients with different RVD grades ( P < 0.05). HER2 positive rates showed an increasing trend following RVD upgrading ( P 𝑡𝑟𝑒𝑛𝑑 < 0.05). HER-2 positive rate in RVD D1 + D2 was 7.69%, which was higher than that in D3 + D4 ( P < 0.05). The ER and Ki-67 expressions in patients were markedly different among DASD ( P = 0.009 and 0.002) and RVD ( P = 0.012 and 0.036) with different grades. The kappa value of each DASD to RVD was 0.31 ( P < 0.01). The RVD 3 proportion was 14.58% (63/432) in HER2 Over-expressing subtype, which was apparently higher than RVD1 (2.43%, 1/41) ( P < 0.05). Breast density may be partial correlated with molecular pathology in breast cancer. [ABSTRACT FROM AUTHOR]

Molecular apocrine breast cancer (MABC) has a distinct hormonal profile, being estrogen receptor (ER) and progesterone receptor (PR) negative but androgen receptor (AR) positive. The clinical significance of MABC and its relative variables have not been absolutely clarified and remain to be determined. Five hundred cases of invasive breast carcinoma were randomly selected in this study, including 158 MABC cases and 342 nonMABC cases. Expression of ER, PR, epidermal growth factor receptor 2 (HER2), Ki67, AR, gross cystic disease fluid protein 15 (GCDFP15), and heat shock protein 27 (HSP27) were analyzed by immunohistochemistry. Differences of continuous variables between MABC and nonMABC subgroups were evaluated by the chi-square test. The Kaplan-Meier method was performed to evaluate disease-free survival (DFS) and overall survival (OS). The MABC subgroup had higher histological grade, bigger tumor size, more lymph node metastasis, and higher pTNM stage than the nonMABC subgroup ( P < 0.05), and patients with MABC had poorer prognosis than those of the nonMABC subgroup ( P < 0.05). Both GCDFP15 and HSP27 were expressed differently in the MABC and nonMABC subgroups ( P < 0.05). Furthermore, in the MABC subgroup, positive HSP27 expression indicated higher risk of recurrence ( P < 0.05) and positive GCDFP15 expression was also a poor marker for patient outcome ( P < 0.05). MABC patients with HSP27 and GCDFP15 co-expression had worse outcome ( P < 0.05). Our data suggested that MABC had a high risk of recurrence. Positive expression of both GCDFP15 and HSP27 were correlated with MABC malignancy. Targeting AR and HSP27 at the same time might offer a useful strategy to MABC. [ABSTRACT FROM AUTHOR]

The aim of this study was to examine the association between molecular subtype (MST) and prognosis and research the postmastectomy radiotherapy (PMRT) effect in T1-T2 tumors with 1-3 positive axillary lymph nodes (ALNs). This retrospective study studied breast cancer patients with T1-T2 tumors and 1-3 positive ALNs according to MST: Luminal A, Luminal B, human epidermal growth factor receptor-2 (Her-2) positive, and Triple negative. The impact of adjuvant PMRT in T1-T2 tumors with 1-3 positive ALNs was also assessed. This study included 1369 patients: 33.0 % Luminal A, 42.9 % Luminal B, 11.9 % Her-2 positive, and 12.2 % Triple negative. On univariate and multivariate analyses, MST was associated with locoregional relapse (LRR). Kaplan-Meier analysis showed that PMRT significantly decreased LRR risk ( p = 0.017) and distant metastasis (DM) risk ( p < 0.0001). In subgroup analysis, PMRT showed significant benefits of improvement in LRR in patients with younger age, positive lymphovascular invasion (LVI), and ratio of positive lymph nodes (LNs) >25 %. Moreover, the nomogram could more accurately predict LRR (c-index 0.75) in T1-2N1 breast cancer patients. MST associated with patient outcomes in breast cancer patients with T1-T2 tumors and 1-3 positive ALN. It makes sense to offer PMRT for patients aged<40 years old, LVI, 2 and 3 positive lymph nodes, and ratio of positive LNs >25 %. [ABSTRACT FROM AUTHOR]

Acquired resistance to lapatinib, a human epidermal growth factor receptor 2 kinase inhibitor, remains a clinical problem for women with human epidermal growth factor receptor 2-positive advanced breast cancer, as metastasis is commonly observed in these patients. Niclosamide, an anti-helminthic agent, has recently been shown to exhibit cytotoxicity to tumor cells with stem-like characteristics. This study was designed to identify the mechanisms underlying lapatinib resistance and to determine whether niclosamide inhibits lapatinib resistance by reversing epithelial-mesenchymal transition. Here, two human epidermal growth factor receptor 2-positive breast cancer cell lines, SKBR3 and BT474, were exposed to increasing concentrations of lapatinib to establish lapatinib-resistant cultures. Lapatinib-resistant SKBR3 and BT474 cells exhibited up-regulation of the phenotypic epithelial-mesenchymal transition markers Snail, vimentin and α-smooth muscle actin, accompanied by activation of nuclear factor-кB and Src and a concomitant increase in stem cell marker expression (CD44 high /CD24 low ), compared to naive lapatinib-sensitive SKBR3 and BT474 cells, respectively. Interestingly, niclosamide reversed epithelial-mesenchymal transition, induced apoptosis and inhibited cell growth by perturbing aberrant signaling pathway activation in lapatinib-resistant human epidermal growth factor receptor 2-positive cells. The ability of niclosamide to alleviate stem-like phenotype development and invasion was confirmed. Collectively, our results demonstrate that lapatinib resistance correlates with epithelial-mesenchymal transition and that niclosamide inhibits lapatinib-resistant cell viability and epithelial-mesenchymal transition. These findings suggest a role of niclosamide or derivatives optimized for more favorable bioavailability not only in reversing lapatinib resistance but also in reducing metastatic potential during the treatment of human epidermal growth factor receptor 2-positive breast cancer. [ABSTRACT FROM AUTHOR]

Chemotherapy-resistant breast cancer displays aggressive clinical behavior, is poorly differentiated and is associated with the occurrence of epithelial-mesenchymal transition and the presence of cancer stem cells. The anthelmintic drug niclosamide has been shown to have numerous clinical applications in the treatment of malignant tumors, in addition to its traditional use in tapeworm disease. Our previous study demonstrated that niclosamide had an antiproliferative effect and could inhibit the stem-like phenotype of the breast cancer cells, suggesting that it might have the potential to be used in the treatment of triple-negative breast cancer. However, the specific function and underlying mechanism of action of niclosamide in chemoresistant human epidermal growth factor receptor 2 (HER2)-positive breast cancer remain unknown. The present study aimed to determine whether niclosamide can inhibit cell proliferation, invasion and epithelial-to-mesenchymal transition, as well as the stem-like phenotype in cisplatin-resistant HER2-positive breast cancer. Alamar Blue and Annexin V/7-AAD staining, mammosphere formation and Transwell assays were performed to assess the viability, apoptosis, stem-like phenotype and invasion ability of breast cancer cell lines, respectively. Signaling molecule expression was detected via western blotting and a xenograft model was used to verify the inhibitory effect of niclosamide in vivo. The results from the present study demonstrated that niclosamide inhibited the resistance of HER2-positive breast cancer to cisplatin both in vitro and in vivo. Furthermore, niclosamide combined with cisplatin could inhibit breast cancer cell invasion, epithelial-mesenchymal transition and cell stemness. The inhibitory effect of niclosamide was mediated by apoptosis induction and Bcl-2 downregulation. Taken together, the results of the present study suggested that niclosamide combined with cisplatin may be considered as a novel treatment for chemoresistant HER2-positive breast cancer. [ABSTRACT FROM AUTHOR]

Background: The most striking feature of molecular apocrine breast cancer (MABC) is the expression of androgen receptor (AR). We report here the mechanism of the AR in regulating the behavior of MABC. Methods: The MABC cell line, MDA-MB-453, and the nonMABC cell line, MCF7, were used in this study. The effect of dihydrotestosterone (DHT) and heat shock protein 27 (HSP27) on cell proliferation was quantified using the cell counter kit-8 (CCK8) and clonogenic assays in vitro and by a xenograft tumor model in vivo. The expression of the AR and HSP27 was analyzed using western blot, qPCR, and immunofluorescence assays. Complexes of the AR and HSP27 were detected by co-immunoprecipitation (Co-IP). Results: In MDA-MB-453 cells, DHT promoted cell proliferation and stimulated AR and HSP27 translocation from the cytoplasm to the nucleus, whereas, it inhibited MCF7 cell growth, and only the AR translocated into the nucleus. HSP27 knock-down decreased the proliferative ability of MDA-MB-453 cells, which could be rescued by DHT, while HSP27 and DHT had synergistic effects on MCF7 cells. HSP27 phosphorylation was a prerequisite for AR translocation into the nucleus, especially phosphorylation on serine 82. In addition, DHT stimulated the tumorigenic and metastatic capacities of MDA-MB-453 cells, while HSP27 knock-down decreased the rate of tumor formation and induced apoptosis in cells. Conclusions: The results suggest that HSP27 assists the AR in regulating the malignant behavior of MABC, and these findings might be helpful in the treatment of MABC. [ABSTRACT FROM AUTHOR]

FAT1 and β-catenin are important tumor regulatory factors. The aim of this study was to detect the possible disparity in their expression from ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) and to explore its correlation with clinicopathological factors. We used immunohistochemistry to detect protein expression of FAT1 and β-catenin in breast cancer tissues from 113 cases of DCIS and 149 cases of IDC. As compared with DCIS, expression of FAT1 and β-catenin were significantly decreased in IDC ( P < 0.05). In addition, our study also revealed a correlation between their expression and some clinicopathological factors. We found that FAT1 expression was associated with nuclear grade and comedonecrosis ( P < 0.05) in DCIS, whereas FAT1 expression showed significant variation with histological grade and LN status ( P < 0.05) in IDC. Similar associations were observed in the β-catenin subgroup. Furthermore, expressions of FAT1 and β-catenin were correlated with each other in DCIS and IDC ( P < 0.05). FAT1(−), β-catenin(−), or FAT1(−)/β-catenin(−) may indicate worse DFS and OS in breast cancer ( P < 0.05). This study suggests that loss of FAT1 and β-catenin are associated with breast cancer progression, aggressive behavior, and poor prognosis. FAT1 alone or together with β-catenin might be a valuable biomarker in predicting the prognosis of patients with breast cancer. [ABSTRACT FROM AUTHOR]