Abstract
Non-coding RNAs (ncRNAs) are regulators of intracellular and intercellular signaling in breast cancer. ncRNAs modulate intracellular signaling to control diverse cellular processes, including levels and activity of estrogen receptor α (ERα), proliferation, invasion, migration, apoptosis, and stemness. In addition, ncRNAs can be packaged into exosomes to provide intercellular communication by the transmission of microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) to cells locally or systemically. This review provides an overview of the biogenesis and roles of ncRNAs: small nucleolar RNA (snRNA), circular RNAs (circRNAs), PIWI-interacting RNAs (piRNAs), miRNAs, and lncRNAs in breast cancer. Since more is known about the miRNAs and lncRNAs that are expressed in breast tumors, their established targets as oncogenic drivers and tumor suppressors will be reviewed. The focus is on miRNAs and lncRNAs identified in breast tumors, since a number of ncRNAs identified in breast cancer cells are not dysregulated in breast tumors. The identity and putative function of selected lncRNAs increased: nuclear paraspeckle assembly transcript 1 (NEAT1), metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), steroid receptor RNA activator 1 (SRA1), colon cancer associated transcript 2 (CCAT2), colorectal neoplasia differentially expressed (CRNDE), myocardial infarction associated transcript (MIAT), and long intergenic non-protein coding RNA, Regulator of Reprogramming (LINC-ROR); and decreased levels of maternally-expressed 3 (MEG3) in breast tumors have been observed as well. miRNAs and lncRNAs are considered targets of therapeutic intervention in breast cancer, but further work is needed to bring the promise of regulating their activities to clinical use.
Highlights
Breast cancer is the most commonly diagnosed cancer and second leading cause of cancer death among women in the United States (U.S.)
Most primary breast tumors are ER+/PR+/HER2, and patients are treated with surgery, radiation, and endocrine therapies Endocrine therapies employ aromatase inhibitors (AI), e.g., letrozole, to block the conversion of androgens to estrogens, or tamoxifen (TAM), which is a selective ER modulator (SERM) that competes with estrogens, including estradiol (E2) for binding ER
25–40% of metastatic tumors in breast cancer patients treated with AIs show ESR1 mutations within the ligand binding domain (LBD) [6]
Summary
Breast cancer is the most commonly diagnosed cancer and second leading cause of cancer death among women in the United States (U.S.). 25–40% of metastatic tumors in breast cancer patients treated with AIs show ESR1 mutations within the ligand binding domain (LBD) [6] These mutations result in the ligand-independent transcriptional activity of the mutant ERα and reduce the efficacy of ER antagonists, including the selective ER downregulators (SERDs) fulvestrant, AZD9496, RU-58688, and GDC-0810 [7]. The remaining ncRNAs, including circular RNA (circRNA), small nuclear RNA (snRNA), small nucleolar RNA (snoRNA), miRNA, and lncRNA together account for ~1% of total ncRNA. Despite their low abundance, these ncRNAs play critical roles in transcription, post-transcriptional processing, and translation [21]. Other studies show that alterations in snoRNAs may promote carcinogenesis and favor caner stem cell phenotypes [71]
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