Androgen receptor decreases CMYC and KRAS expression by upregulating let-7a expression in ER−, PR−, AR+ breast cancer

Abstract

It is generally known that the decision to use anti-estrogen therapy is based on the expression of estrogen and progesterone receptors in breast cancers. Recent studies have shown that androgen receptor (AR) is frequently expressed in ER-, PR- breast cancer and plays an important role in the prognosis of breast cancer patients. Furthermore, AR can increase the global expression of microRNAs, post-transcriptional gene regulators that play a crucial role in the initiation and progression of breast cancer. In this study, we investigated the functions and relations of AR, related miRNAs and target proteins in ER-, PR-, AR+ breast cancer. The results showed that androgen-induced AR activating signal directly upregulates let-7a expression, downregulates CMYC and KRAS protein expression, and inhibits cell proliferation in ER-, PR-, AR+ breast cancer cells. Overexpression of let-7a inhibits cell proliferation and downregulates CMYC and KRAS protein expression, whereas inhibition of let-7a expression by specific antisense oligonucleo-tides increases cell growth and upregulates CMYC and KRAS protein expression. We performed in situ hybridization for let-7a and immunohistochemical staining for CMYC and KRAS using sequential sections obtained from surgically-resected breast cancer tissues and observed an inverse correlation between the staining pattern of let-7a and its target proteins. Androgen-induced AR activating signal upregulates let-7a that targets CMYC and KRAS and contributes to ER-, PR-, AR+ breast cancer pathogenesis. Elucidation of this pathway will help develop new therapies.

Androgen receptor and miRNA-126* axis controls follicle-stimulating hormone receptor expression in porcine ovarian granulosa cells

“…In addition, several recent studies showed that AR can indirectly regulate the expression and function of its target gene also via mechanisms involving miRNAs (Ma et al 2013, Lyu et al 2014, Mishra et al 2014, Pasqualini et al 2015. In this study, we found that miR-126* could decrease FSHR expression and increase the rate of apoptosis in pGCs by binding directly to the 3′-UTR of FSHR.…”

“…A recent study demonstrated that androgens attenuate follicular atresia by increasing expression of miR-125b, which in turn suppresses the expression of proapoptotic proteins (Sen et al 2014). Several studies also showed that androgens and AR control their target genes by regulating the expression of miRNAs (Ma et al 2013, Lyu et al 2014, Pasqualini et al 2015. To date, however, the regulatory relationship between AR, miRNAs, and FSHR in GCs has not been fully elucidated.…”

Evidence of androgen action in endometrial and ovarian cancers

“…The authors report that mRNA expression levels and KRAS amplification were increased significantly in metastatic compared with primary lesions consistent with involvement of KRAS alterations in disease progression (Birkeland et al 2012). In a recent study, KRAS protein expression was reported to be decreased by AR signalling in ERK, PRK and ARC breast cancer cells (Lyu et al 2014), which may indicate a further target for androgen therapy in EC.…”

Bringing androgens up a NOTCH in breast cancer

“…However, it is currently unclear how to stratify individual breast cancers based on whether they will respond favourably to androgen treatment or not. In different breast cancer cell lines, modulation of androgen signalling can have growth-inhibitory or growth-promoting effects (Birrell et al 1995, Ortmann et al 2002, Greeve et al 2004, Lyu et al 2014, reviewed in Fioretti et al (2014), and this extends to the applicability of AR expression as a prognostic marker in specific subtypes of breast cancer (Kuenen-Boumeester et al 1996, Agoff et al 2003, Peters et al 2009, Kraus et al 2010, Gasparini et al 2014. Such conflicting reports/data raise concerns for the clinical efficacy of androgen modulation in breast cancer.…”