Roles for miRNAs in endocrine resistance in breast cancer

Abstract

Therapies targeting estrogen receptor alpha (ERα), including selective ER modulators such as tamoxifen, selective ER downregulators such as fulvestrant (ICI 182 780), and aromatase inhibitors such as 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 microRNAs (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.

Keywords: antiestrogen; aromatase inhibitor; breast cancer; endocrine-resistance; estrogen receptor; miRNA; tamoxifen.

Figure 1. Summary of the molecular mechanisms promoting acquired endocrine resistance

Activation and or amplification of receptor RTKs including insulin-like growth factor receptor (IGFR), epidermal growth factor receptor (EGFR), and HER2 have been detected in tamoxifen-resistant breast cancer cells and endocrine-resistant patient tumors. Plasma membrane-associated GPER and ERα, including splice variants ERα36 ERα46, are increased in endocrine-resistant breast cancer cells and tumors. Activation of these receptors activate intracellular signaling cascades including MAPK and PI3K/AKT pathways that ultimately increase transcription of genes that promote growth and survival and resistance to apoptosis. Additionally, these pathways increase ligand-independent ERα activation by phosphorylation. Alternatively, MAPK and PI3K/AKT can directly promote expression of non-ERE responsive genes by activating other transcription factors, e.g., AP-1, not shown here. Promoter methylation of CpG islands and histone deacetylation has been shown to repress ERα expression and promote endocrine resistance. Abbreviations: Estrogen receptor α (ERα), estrogen response element (ERE), G protein-coupled estrogen receptor (GPER), plasma membrane (PM), retinoblastoma (RB), V-Myc Avian Myelocytomatosis Viral (MYC), B-cell lymphoma (BCL), homologous antagonist killer (BAK), BCL-2-interacting killer (BIK)

Figure 2. Established targets of miRNAs in endocrine resistant breast cancer

miRNAs associated with ERα signaling, growth factor/RTK signaling, EMT, dysregulation of cell cycle kinetics, and apoptosis and their targets in these pathways involved in endocrine resistance are shown. The miRNAs and their targets are described in the text and summarized in Tables 1 and 2. The established, bona fide targets are indicated with solid black lines. The dotted arrows indicate observed correlations with unknown mechanisms.

Figure 3. Higher expression of AGO2 is statistically associated with decreased relapse-free survival in all breast cancer and in patients whose primary tumors are ERα+/PR+

The Kaplan-Meier plots of AGO2 expression in breast tumors with breast cancer survival were generated using http://kmplot.com/analysis/index.php?p=service (Gyorffy, et al. 2010). A) All breast tumors, n = 3557; B) ERα+/PR+, n = 701.