Direct regulation of microRNA biogenesis and expression by estrogen receptor beta in hormone-responsive breast cancer

Abstract

Estrogen effects on mammary epithelial and breast cancer (BC) cells are mediated by the nuclear receptors ERa and ERb, transcription factors that display functional antagonism with each other, with ERb acting as oncosuppressor and interfering with the effects of ERa on cell proliferation, tumor promotion and progression. Indeed, hormone-responsive, ERa þ BC cells often lack ERb, which when present associates with a less aggressive clinical phenotype of the disease. Recent evidences point to a significant role of microRNAs (miRNAs) in BC, where specific miRNA expression profiles associate with distinct clinical and biological phenotypes of the lesion. Considering the possibility that ERb might influence BC cell behavior via miRNAs, we compared miRNome expression in ERb þ vs ERbÀ hormone-responsive BC cells and found a widespread effect of this ER subtype on the expression pattern of these non-coding RNAs. More importantly, the expression pattern of 67 miRNAs, including 10 regulated by ERb in BC cells, clearly distinguishes ERb þ , node-negative, from ERbÀ, metastatic, mammary tumors. Molecular dissection of miRNA biogenesis revealed multiple mechanisms for direct regulation of this process by ERb þ in BC cell nuclei. In particular, ERb downregulates miR-30a by binding to two specific sites proximal to the gene and thereby inhibiting pri-miR synthesis. On the other hand, the receptor promotes miR-23b, -27b and 24-1 accumulation in the cell by binding in close proximity of the corresponding gene cluster and preventing in situ the inhibitory effects of ERa on pri-miR maturation by the p68/DDX5-Drosha microprocessor complex. These results indicate that cell autonomous regulation of miRNA expression is part of the mechanism of action of ERb in BC cells and could contribute to establishment or maintenance of a less aggressive tumor phenotype mediated by this nuclear receptor.

Post-transcriptional Regulation of Human Breast Cancer Cell Proteome by Unliganded Estrogen Receptor β via microRNAs

“…Both ERs were found to bind in vivo to miRNA gene regulatory sites in BC cell chromatin upon activation by E2 (8,26) and to control BC cell miRNome activity in vitro and in vivo (27,28). This result is particularly intriguing in view of the known master regulatory role of these RNAs in normal and transformed cells.…”

miRNA biogenesis: Biological impact in the development of cancer

“…In breast cancer, ERb down-regulates miR-30a inhibiting pri-miRNA polymerization, while ERa, but not ERb, shows inhibitory effects over the maturation of the pri-miRNA cluster miR-23b/27b/24-1 through its direct binding to the p68/p72 Drosha microprocessor complex, which can be activated by E2. 93 A Recent study reported that E2 negatively regulates the expression of miR-30c in endometrial cancer cells, likely through prevention of miRNA maturation. 94 Moreover, the androgen receptor, an important tumorigenic player in prostate cancer, induces the transcription of miR-23a, miR-27a and miR-24-2, but more significantly accelerates primiR-23a/27a/ 24-2 cluster processing.…”

Expression of miR-18a and miR-210 in Normal Breast Tissue as Candidate Biomarkers of Breast Cancer Risk

“…In breast cancer, growing evidence shows loss of tumor suppressor miRNAs results in enhanced expression of target oncogenes (7), whereas increased expression of oncogenic miRNAs (known as Oncomirs) can repress target tumor suppressor genes (8). The role of miRNAs in breast cancer progression and biology demonstrates that the expression of specific miRNAs correlates with features such as estrogen receptor (ER) and progesterone receptor (PR) expression (9,10) and other key features such as cell proliferation, cell cycle, invasion, and metastasis (11)(12)(13).…”