Research On The Function Of Androgen Receptor And Its Relative Molecular In Breast Cancer

Objective: To study the prognostic value of androgen receptor(AR) and its related molecules, and the correlation of the expression of all these biomarkers in breast ductal carcinoma(IDC) with different ER status. To further study the implication of different AR status on the expression of let-7a and its relative molecular HMGA2 and p STAT3 in ER negative breast cancer cell line.Methods: We retrospectively investigated 240 women with invasive(but not carcinoma in situ, recurrent, metastatic, bilateral or non-epithelial) breast cancers, who were treated at our institution between January 2008 and December 2009. We immunohistochemically assessed expression of AR and metastasis-associated protein-1(MTA1) in ER+(n=120) and ER-(n=120) breast cancer specimens. We utilized MDA-MB-231 for detecting the correlation between AR and let-7a in ER negative breast cancer cell. We used immunofluorescence to detect if AR is expressed in this cell line. Stable androgen receptor down regulation cells was established by lentivirus gene knockout. Then colony formation assay and MTT were used to study the proliferation of MDA-MB-231 cell line. Western Blot and q RT-PCR were used to check the expression of AR, let-7a, HMGA2 and p STAT3.Results: Among the 240 specimens, 59.2%(n=142) expressed AR and 36.7%(n=88) had high MTA1 expression(MTA1High). MTA1 High was significantly expressed in ERtumors with AR+/HER2+ co-expression(P<0.01), and AR/HER2 co-expression was essential for MTA1 High expression in ER- tumors(P<0.01). With a median follow-up of 74 months, AR was positively associated with disease-free survival(DFS) in ER+ tumors(P=0.011). In ER- tumors, MTA1 was negatively related to DFS(P=0.006); patients with AR+/HER2+ tumors also showed poorer outcomes(P<0.01). In Cox's models, AR expression and lymph node status were independent predictors for DFS in ER+ cancers, whereas AR/HER2 co-expression and lymph node status were independent predictors for DFS in ER- cancers. We demonstrated that AR could be an additional marker for endocrine responsiveness in ER+ cancers, and blocking MTA1 might be an effective way to inhibit AR/HER2 signaling in ER- breast cancers. AR was highly expressed in MDA-MB-231 cell line as shown by immunofluorescence. The result of MTT showed the ability of proliferation of AR-down regulated cell was enhanced, and the same phenomenon was observed in colony formation assay. Let-7a expression was only 30% compared to controls. The result of Western Blot showed the expression of HMGA2 and phosphorylated p STAT3 was significantly lower in AR-down regulated group than the control cells. The results of MTT and colony formation assay showed the ability of proliferation of double-infected cells were impaired compared to AR- down regulated cells. We found the level of let-7a was up regulated in the group infected with lentivirus, and western blot showed the expression of HMGA2 and p STAT3 was down regulated.