MiR-301a-3p Suppresses Estrogen Signaling by Directly Inhibiting ESR1 in ERα Positive Breast Cancer

Abstract

Background/Aims: MiRNA-301a-3p is an oncogenic miRNA whose expression is associated with tumor development, metastases and overall poor prognosis. Estrogen receptor α (ERα) is one of the estrogen hormone-activated transcription factors, which regulates a large number of genes and is involved in the mammary gland development. Expression of ERα is considered to be a good indicator for endocrine therapy and breast cancer survival. Loss of ERα in breast cancer patients indicates invasiveness and poor prognosis. In this study, we focus on the regulation of ERα by miR-301a and its role in transition from estrogen-dependent to estrogen-independent breast cancer. Methods: Expression of miR-301a-3p was measured by qRT-PCR in tumor tissue samples from 111 patients with primary breast carcinoma and in mammospheres representing in vitro model of cancer stem-like cells. Dual reporter luciferase assay and complementary experiments were performed to validate ESR1 as a direct target of miR-301a-3p. The effect of miR-301a-3p on estrogen signaling was evaluated on the level of gene and protein expression and growth response to estrogens. Finally, the effect of miR-301a-3p expression on tumor growth was studied in nude mice. Results: We identified ESR1 as a direct target of miR-301a-3p. Ectopic miR-301a-3p causes a decrease in ESR1 mRNA and protein level and modulates the expression of ERα target genes in ERα positive breast cancer cells. Consistently, miR-301a-3p causes a decrease in sensitivity of MCF7 cells to 17β-estradiol and inhibits the growth of estrogen dependent tumor in nude mice. Yet, the mice tumors have significantly increased expression of genes related to cancer stem-like cells and epithelial to mesenchymal transition suggesting enrichment of the population of cells with more invasive properties, in line with our observation that miR-301a-3p expression is highly increased in mammospheres which show a decrease in estrogenic signaling. Importantly, miR-301a-3P level is also increased in primary breast cancer samples exhibiting an ER/PR negative phenotype. Conclusion: Our results confirm ESR1 as a direct target of miR-301a-3p and suggest that miR-301a-3p likely contributes to development of estrogen independence, which leads to a more invasive phenotype of breast cancer.

MiR-130a-3p Inhibits PRL Expression and Is Associated With Heat Stress-Induced PRL Reduction

“…Although the miR-130a-3p inhibitor rescued the reduction of ERα and PRL induced by miR-130a-3p mimic, the inhibitor alone had no significant changes relative to the control. This similar situation of miRNAs inhibitor also happened in previous studies (36,37). One possible reason may be that the endogenous miR-130a-3p level was low in GH3 cells, which limited the effect of miR-130a-3p inhibitor (38).…”

Specific microRNA signatures in exosomes of triple-negative and HER2-positive breast cancer patients undergoing neoadjuvant therapy within the GeparSixto trial

“…Particularly, the quantification of these exosomal miRNAs in a large cohort of plasma samples before, during, and after chemotherapy is required. Since miR-301 regulates the PTEN/Akt and NFκB signaling pathways that are important in the progression of BC [ 43 , 44 ], and binds to estrogen receptor 1 mRNA leading to estrogen independence of BC [ 45 ], miR-301 may be an early therapeutic target molecule in BC.…”

Perspectives on the Role of Non-Coding RNAs in the Regulation of Expression and Function of the Estrogen Receptor

“…The ERα-miR-1271-SNAI2 axis is involved in the regulation of transforming growth factor (TGF)-β-induced breast cancer progression [60]. miR-301a-3p and miR-129 have been shown to inhibit estrogen signaling through direct interaction with ESR1 and ESR2 genes, respectively [61,62]. In addition, miR-148a and miR-22 inhibit ESR1 expression to inhibit the viability and migration of breast cancer cells [63,64].…”