| Part1Objective:To study the correlation of the expression of Androgen receptor (AR) with the clinicopathologic characteristics and prognosis in breast invasive ductal carcinoma (IDC) with different ER status, and to investigate the results of AR as a new guide for endocrine therapy.Methods:During a period from January to December2004, we111cases from ER-positive cases, and113cases from ER-negative cases were randomly allocated into two IDC groups:ER-positive group and ER-negative group. The protein expression of AR,ER, PR, HER-2, Ki67, P53from224IDC cases were assayed using immunohistochemistry. The current study focused on the assessment of protein expressions in the groups (ER+/AR+, ER+/AR-, ER-/AR+, ER-/AR-)and their main characteristics. The study was focused on the ER+and ER-groups and assessed their main characteristics and evaluated the prognositic difference in different AR and ER status cases.Results:The positive rate of AR was67.9%(52/224), and the rate of Arexpression was80.2%(89/111)and55.8%(63/113) in the ER-positive and ER-negative cases, respectively. The AR expression in the ER-positive tumors was associated with tumor size(P=0.015), istological grade(P=0.033), pTNM (P=0.002) and endocrine therapy (P=0.007). The AR expression in ER-negative tumors was associated with the histological grade of tumor (P=0.039), HER2overexpression (P=0.039), and postmenopausal status (P=0.016).The univariate analysis showed that the patients with AR-positive tumors in the ER-positive and ER-negative groups had significantly better disease-free survival than thoes with AR-negative tumors (P<0.001, P=0.046). The COX regression analysis revealed that AR expression is an independent prognostic factor in the224IDC cases and ER-positive group.Conclusions:AR is expressed in a significant number of different ER states breast cancer and shows significant associations with important clinical hormone therapy and pathologic prognostic factors. Especially AR is the potential role in clinical management of women with ER-negative breast carcinomas. Part2Objective:It is well known that sex steroids are involved in the growth of breast cancers, and the high majority of breast carcinomas express estrogen, progesterone and androgen receptors. Androgens inhibit the growth of breast cancer cells in vitro and in vivo by mechanisms that remain poorly defined. In order to understand how androgen receptor and miR-let-7a regulate the cell proliferation in ER-positive breast cancer, the activation of AR could up-regulated miR-let-7a expression, but the regulation mechanisms remain poorly defined.Methods:The RNA was isolated from the human breast cancer MCF7cells after stimulation with10-8mol/L DHT or without, and RT-PCR was performed to obtain the cDNA. Real-time PCR was applied to detect the expression of miR-let-7a at mRNA level respectively in MCF7cells. The MCF7cells were transfected with pcDNA3/pri-miR-let-7a or miR-let-7a antisense oligonucleotides (ASOs), we observeed the effects of miR-let-7a miRNA on cell proliferation in MCF-7cell line by MTT assays and FCM analysis. We checked the protein expression levels of ER-a, k-ras and c-Myc after transfection of mimics of miR-let-7a in the MCF-7cell line using the western blot assays.Results:In this stud), we found that miR-let-7a is post-transcriptionally regulated by androgen in breast cancer cells. miR-let-7a miRNAs were up-regulated in ER-positive human MCF-7breast cancer cells after the stimulation with10-8mol/L DHT. We also identified overexpression miR let-7a of decreased c-Myc, k-Ras, ER-α poteins antiproliferate in MCF7cells. The c-Myc, k-Ras, ER-α as direct target gene for miR-let-7a, the protein level of them were inversely correelated with the miR-let-7a expression level. Our results demonstrate that miR-let-7a can inhibit the growth activity of MCF-7breast cancer cells in vitro. Let-7is also considered as a tumor suppressor to inhibit malignant growth of cancer cells by targeting RAS, HMGA2, and c-Myc.Conclusions:The downregulation of c-Myc, k-Ras, ER-a poteins by miR let-7a may explain why the promotion of miR-let-7a can inhibit breast cancer cell proliferation. Our results suggest that miR-let-7a miRNAs could be a novel target for drug therapies that targets only ER-α dependence in breast cancer. Nevertheless, these studies might lead to the future development of an alternative strategy that targeting at miR-let-7a in treatment of diseases, it is an new oncogenes and suooressors, new prognostic factors and potential therapentic targets. For ER-α-positive breast cancer, miR-let-7a miRNAs could be candidate targets for drug therapies in the future. |
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