Kaiso regulates tumor-suppressing microRNA-31 and microRNA-200c in triple negative breast cancer (TNBC) cells

Abstract

Breast cancer (BC) is a leading cause of death among women worldwide. Despite a recent decline in BC rates due to improved detection and therapeutic options, women diagnosed with the triple negative breast cancer (TNBC) subtype have a poor prognosis relative to other BC subtypes. As TNBCs do not express the estrogen receptor (ER), progesterone receptor (PR), or human epidermal growth factor receptor-2 (HER2) that are commonly targeted in hormone positive subtypes, they have limited treatment options. While some progress has been made at unraveling the molecular mechanisms behind TNBC, there is still a large knowledge gap regarding how these tumors initiate and progress in such an aggressive manner. Increasingly, the role of microRNA deregulation has been linked to TNBC tumorigenesis. Recently, the transcription factor Kaiso was implicated in the regulation of the pleiotropically acting microRNA-31 (miR-31) and tumor-suppressing microRNA-200c (miR-200c) that promote tumor migration and invasion in prostate cancer. Notably Kaiso is highly expressed in TNBC, relative to other BC subtypes, and high Kaiso expression correlates with poor survival. Herein, we show that Kaiso expression is inversely correlated with miR-31 and miR-200c expression in the TNBC cell lines (MDA-MB-231 and Hs578T). Upon Kaiso depletion, there is an increased expression of these microRNAs and reduced expression of their downstream targets. Misexpression of miR-31 and miR-200c in parental and Kaiso-depleted TNBC cells affects their migratory ability. We also show that Kaiso associates with the promoter regions of both miR-31 and miR-200c. Collectively, these results imply that Kaiso is a regulator of miR-31 and miR-200c, which are important suppressors of epithelial mesenchymal transition (EMT) but are highly downregulated in TNBC. Our findings reveal a novel mechanism for Kaiso in the promotion of TNBC tumorigenesis.