Androgen receptor and heat shock protein 27 co-regulate the malignant potential of molecular apocrine breast cancer.

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.

The importance of EGFR as a biomarker in molecular apocrine breast cancer.

Molecular apocrine breast cancer (MABC) is a molecular subtype with a poor prognosis, and there is urgent need to find new therapeutic targets. Epidermal growth factor receptor (EGFR) plays an important part in regulating the biological behavior of tumor cells, and EGFR-targeted drugs have already been used in therapy for lung and colorectal cancers. The purpose of this study was to analyze the significance of EGFR expression in MABC. A total of 400 patients with invasive breast cancer were analyzed, including 200 MABC and 200 non-MABC cases. Immunohistochemistry and immunofluorescence were carried out to evaluate the expression of estrogen receptor, progesterone receptor, androgen receptor (AR), EGFR, epidermal growth factor receptor 2 (HER2), and other biomarkers. Two hundred twelve (53%) cases were positive for EGFR expression, including 173 MABC and 39 non-MABC cases. EGFR expression was positively associated with AR expression in MABC, as well as with more advanced tumor stage and high Ki67 expression. Patients with EGFR expression had worse outcomes than those without. As a prognosis biomarker, EGFR was significantly associated with poorer clinical outcomes, and the co-expression of EGFR and HER2 often predicted worse outcomes in MABC. This study suggests that the identification of new targets such as HER2 and EGFR may help with assessing the prognosis of patients with MABC. Using both AR and EGFR as therapeutic targets may be especially important in MABC and may help to guide the choice of suitable treatments for individual breast cancer patients.

Heat shock protein 27 and gross cystic disease fluid protein 15 play critical roles in molecular apocrine breast cancer.

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.