RUNX1 suppresses breast cancer stemness and tumor growth

Abstract

Recent studies have revealed that mutations in the transcription factor Runx1 are prevalent in breast tumors. Yet, how loss of Runx1 contributes to breast cancer (BCa) remains unresolved.We demonstrate for the first time that Runx1 represses the breast cancer stem cell (BCSC) phenotype and consequently, functions as a tumor suppressor in breast cancer. Runx1 ectopic expression in MCF10AT1 and MCF10CA1a BCa cells reduces (60%) migration, invasion and in vivo tumor growth in mouse mammary fat pad (P<0.05). Runx1 is decreased in BCSCs, and overexpression of Runx1 suppresses tumorsphere formation and reduces the BCSC population. Furthermore, Runx1 inhibits Zeb1 expression, while Runx1 depletion activates Zeb1 and the epithelial-mesenchymal transition. Mechanistically Runx1 functions as a tumor suppressor in breast cancer through repression of cancer stem cell activity. This key regulation of BCSCs by Runx1 may be shared in other epithelial carcinomas, highlighting the importance of Runx1 in solid tumors. Introduction:Breast tumors are heterogeneous, as they are comprised of several types of cells, including transformed cancer cells, supportive cells, tumor-infiltrating cells and cancer stem cells (CSC).The CSC is acknowledged to be a significant component of growing tumors (1) (2). As the name implies, CSC can self-renew and reconstitute the cellular hierarchy within tumors (3) (4). Moreover, these stem-like cells are highly chemo-resistant and metastatic (5) (6).Significantly, signaling pathways (TGF-β, WNT, Hedgehog and Notch) and transcription factors (Snail, Twist and Zeb) regulating stemness properties in CSC are involved in controlling an essential cellular process designated epithelial-mesenchymal transition (EMT) (7,8). The EMT process is linked to chemo-resistance and cancer metastasis (9, 10) (11). One such example is Zeb1, a well-known EMT-activator that is also a key factor for cell plasticity and promotes stemness properties in breast and pancreatic cancers (12) (13). However there remains a compelling requirement to understand regulatory mechanisms that contribute to and sustain the stemness of the CSC population. By identifying regulator(s) that maintain or repress the cancer stem cell phenotype can provide insights for novel therapeutic approaches. Recently, a list of 40 mutation-driver genes for which deregulation contributes directly to breast tumor progression has been identified (14); among these is the transcription factor RUNX1, which has been shown to repress EMT. Here we address for the first time, the function of RUNX1 in regulating breast cancer stem cells.The Runx family, including RUNX1, Runx2 and Runx3, are evolutionarily conserved transcription factors and function as critical lineage determinants of various tissues (15).

An active RUNX1-ID1/ID3 axis governs differentiation and chemoresistance of cancer stem cell population in epithelial ovarian cancer cells

“…RUNX1 mediated suppression of negative regulators of STAT3 signaling SOCS3 and SOCS4 was shown to be essential for tumor initiation and maintenance of CSCs (Scheitz et al, 2012). RUNX1 is known to suppress the CSC phenotype in estrogen/progesterone-positive breast carcinoma by direct inhibition of ZEB1 expression (Hong et al, 2018). RUNX1 is also known to be overexpressed in ovarian tumor samples, moreover hypomethylation of RUNX1 gene post chemotherapy has been observed in OC (Keita et al, 2013).…”