miRNA-mRNA interaction network regulating chemotherapy resistance in triple negative breast cancer

Abstract

Triple negative breast cancer (TNBC) is the most aggressive breast cancer subtype, lacking the expression of the estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER2). Compared to other subtypes, which can be treated with targeted therapies, chemotherapy is the major regimen used to treat TNBCs. Moreover, TNBC patients have better response rate to chemotherapy compared to other breast cancer (BC) subtypes. However, patients develop resistance rapidly, which in turn significantly increases the mortality rate. Therefore, there is urgent unmet need for elucidating the mechanisms of chemotherapy resistance in TNBC and identifying novel targets that can overcome resistance or potentiate the efficacy of chemotherapy. In this line, we developed an in vivo chemoresistant TNBC xenograft model, performed whole transcriptome sequencing of these tumors, and built a miRNA-mRNA interaction network regulating TNBC chemoresistance. We identified an ECM glycoprotein (“EG”) as the central chemoresistance driver gene, and a candidate potential tumor suppressor miRNA (“TSM”) sensitizing cells to EG-induced chemoresistance. Mechanistically, TSM was downregulated by hypoxia in chemoresistant tumor microenvironment that, in turn, led to upregulation of an integrin family protein (“IFP”), which encodes a subunit of receptor recognizing EG. We further showed that TSM directly binds the 3’-UTR of IFP, represses its expression, and inhibits FAK/Src signaling, PI3K signaling and MAPK signaling pathways, which constitute the major pathways in cell survival. Importantly, overexpression of TSM or inhibition of the IFP overcame EG-driven chemotherapy resistance in vitro and potentiated the efficacy of chemotherapy in vivo. Overall, we built the first miRNA-mRNA interaction network of TNBC chemoresistance and identified a hypoxia-regulated novel tumor suppressor miRNA, TSM, or its target IFP as potential targets overcoming chemoresistance or potentiating the efficacy of chemotherapy in TNBCs.