Deletion of Tip30 leads to rapid immortalization of murine mammary epithelial cells and ductal hyperplasia in the mammary gland

Abstract

Transformation of mammary epithelial cells (MECs) from the normal to the neoplastic stage requires the dysregulation of tumor suppressor genes and proto-oncogenes. Tip30 is a tumor suppressor that can inhibit estrogen receptor-mediated transcription in MECs, but its role in MEC proliferation remains unknown. Here, we show that deleting the Tip30 gene leads to ductal hyperplasia in mouse mammary glands early in life and extensive mammary hyperplasia with age. Tip30(-/-) mammary glands transplanted into wild-type mammary fat pads also display mammary trees with extensive ductal hyperplasia. Strikingly, Tip30 deletion promotes proliferation of primary MECs and results in rapid immortalization of MECs in vitro relative to wild-type cells. Gene array analysis identified significant increases in the expression of mammary epithelial growth factors Wisp2 and Igf-1 in Tip30(-/-) cells. Knockdown of either Wisp2 or Igf-1 using short interfering RNA dramatically inhibited proliferation of Tip30(-/-) cells. Together, these results suggest that Tip30 is an intrinsic and negative regulator of MEC proliferation partly through the inhibition of Wisp2 and Igf-1 expression, and its absence in the mammary gland may predispose MECs to neoplastic transformation.