Roles for miRNAs in endocrine resistance in breast cancer

Abstract

Therapies targeting estrogen receptor α (ERα) including selective estrogen receptor modulators (SERMs), e.g., tamoxifen; selective estrogen receptor downregulators (SERDs), i.e., fulvestrant (ICI 182,780); and aromatase inhibitors (AI), e.g., letrozole, are successfully used in treating breast cancer patients whose initial tumor expresses ERα. Unfortunately, the effectiveness of endocrine therapies is limited by acquired resistance. The role of miRNAs in the progression of endocrine-resistant breast cancer is of keen interest in developing biomarkers and therapies to counter metastatic disease. This review focuses on miRNAs implicated as disruptors of antiestrogen therapies, their bona fide gene targets, and associated pathways promoting endocrine resistance.

MicroRNA as Crucial Regulators of Gene Expression in Estradiol-Treated Human Endothelial Cells

“…Cell cycle, cell death and survival have also been ranked in the principal E2-regulated networks. Indeed, E2 has already been implicated in apoptosis via activation of miRNA-23a and p53 in liver cancer [30], and different profiles of estrogen-regulated miRNA in breast cancer cells have been described [31].…”

Non-coding RNAs: long non-coding RNAs and microRNAs in endocrine-related cancers

“…The function of piRNAs and snoRNAs in endocrine-related cancers was reviewed (Venkatesh, et al 2015). miRNAs are best characterized for their gene silencing of target mRNA by complementary base-paring with the 3'UTR within the RNA-induced silencing complex (RISC) to repress translation and/or cause mRNA degradation (Muluhngwi and Klinge 2015). Like miRNAs, siRNAs and piRNAs bind Argonaute (AGO) family members and base pair with target RNA to cause RNA degradation and/or translation repression (Watanabe and Lin 2014).…”

“…The biogenesis of miRNAs has been reviewed (Ha and Kim 2014;Klinge 2015). In brief, in the canonical pathway of miRNA biogenesis, miRNAs are transcribed as primary-micro-RNAs (pri-miRNAs) by RNA pol II either as independent transcription units or are cotranscribed within introns of pre-mRNAs (~ 50% of miRNAs) (Saini et al, 2007).…”

“…There are many recent reviews of the identity, regulation, and targets of miRNAs in BCa, e.g., (Egeland, et al 2015;Klinge 2015;Li, et al 2017c;Muluhngwi and Klinge 2015;O'Bryan, et al 2017;Smith, et al 2017;van Schooneveld, et al 2015;Yahya and Elsayed 2015). miRNAs regulate key pathways dysregulated in BCa including apoptosis, cell cycle, cellular energetics, invasion, metabolism, and metastasis.…”

“…Hence, many miRNA studies have examined the correlation of miRNAs with diagnostic markers related to ERα in BCa, estrogen-regulated miRNAs, and the potential role of miRNAs in endocrine-resistance (Klinge 2015; Muluhngwi and Klinge 2015). ERα is the target of miRNAs including miR-221, miR-222, miR-873, let-7b, and let-7i (reviewed in (Muluhngwi and Klinge 2015)). …”