Elucidating the Role of YTHDF1 in Mammary Gland Development and Breast Tumorigenesis

Abstract

Tumor initiating cells (TICs), or cancer stem cells, are a small subset of cancer cells that possess stem-cell-like properties, which confer malignant advantages that can lead to cancer initiation and progression. Understanding which of these regulatory mechanisms are shared with normal stem cells can therefore deepen our knowledge of TICs and illuminate new modes of therapeutic intervention. Here, we investigate YTHDF1, an RNAbinding protein that recognizes the N6-methyladenosine (m6A) RNA modification, as a potential novel regulator of self-renewal capacity and differentiation in mammary stem cells (MaSCs) and breast TICs. Using breast cancer cell lines depleted for Ythdf1 and Ythdf1-deficient mice, we show YTHDF1 is not necessary for normal mammary gland development, whereas loss of YTHDF1 promotes both mammary gland regrowth and tumorigenesis in vivo. Future mechanistic studies are needed to understand which shared downstream targets of YTHDF1 contribute to regulation of mammary gland regrowth and tumorigenesis. Our study therefore reveals a potentially new common regulator shared between MaSCs and breast TICs.