CDK Inhibitor p18INK4c Is a Downstream Target of GATA3 and Restrains Mammary Luminal Progenitor Cell Proliferation and Tumorigenesis

Xin Hai Pei, Feng Bai, Matthew D. Smith, Jerry Usary, Cheng Fan, Sung Yun Pai, I. Cheng Ho, Charles M. Perou, Yue Xiong

Research output: Contribution to journalArticlepeer-review

61 Scopus citations

Abstract

Mammary epithelia are composed of luminal and myoepithelial/basal cells whose neoplastic transformations lead to distinct types of breast cancers with diverse clinical features. We report that mice deficient for the CDK4/6 inhibitor p18Ink4c spontaneously develop ER-positive luminal tumors at a high penetrance. Ink4c deletion stimulates luminal progenitor cell proliferation at pubertal age and maintains an expanded luminal progenitor cell population throughout life. We demonstrate that GATA3 binds to and represses INK4C transcription. In human breast cancers, low INK4C and high GATA3 expressions are simultaneously observed in luminal A type tumors and predict a favorable patient outcome. Hence, p18INK4C is a downstream target of GATA3, constrains luminal progenitor cell expansion, and suppresses luminal tumorigenesis in the mammary gland.

Original languageEnglish (US)
Pages (from-to)389-401
Number of pages13
JournalCancer Cell
Volume15
Issue number5
DOIs
StatePublished - May 5 2009
Externally publishedYes

Keywords

  • CELLCYCLE
  • STEMCELL

ASJC Scopus subject areas

  • Cancer Research
  • Cell Biology
  • Oncology

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