Dysregulated STAT1-SOCS1 control of JAK2 promotes mammary luminal progenitor cell survival and drives ER+ tumorigenesis

S. R. Chan, C. G. Rickert, W. Vermi, K. C.F. Sheehan, C. Arthur, J. A. Allen, J. M. White, J. Archambault, S. Lonardi, T. M. McDevitt, D. Bhattacharya, M. V. Lorenzi, D. C. Allred, R. D. Schreiber

Research output: Contribution to journalArticlepeer-review

36 Scopus citations


We previously reported that STAT1 expression is frequently abrogated in human estrogen receptor-positive (ER +) breast cancers and mice lacking STAT1 spontaneously develop ER + mammary tumors. However, the precise mechanism by which STAT1 suppresses mammary gland tumorigenesis has not been fully elucidated. Here we show that STAT1-deficient mammary epithelial cells (MECs) display persistent prolactin receptor (PrlR) signaling, resulting in activation of JAK2, STAT3 and STAT5A/5B, expansion of CD61+ luminal progenitor cells and development of ER+ mammary tumors. A failure to upregulate SOCS1, a STAT1-induced inhibitor of JAK2, leads to unopposed oncogenic PrlR signaling in STAT1-/-MECs. Prophylactic use of a pharmacological JAK2 inhibitor restrains the proportion of luminal progenitors and prevents disease induction. Systemic inhibition of activated JAK2 induces tumor cell death and produces therapeutic regression of pre-existing endocrine-sensitive and refractory mammary tumors. Thus, STAT1 suppresses tumor formation in mammary glands by preventing the natural developmental function of a growth factor signaling pathway from becoming pro-oncogenic. In addition, targeted inhibition of JAK2 may have significant therapeutic potential in controlling ER + breast cancer in humans.

Original languageEnglish (US)
Pages (from-to)234-246
Number of pages13
JournalCell Death and Differentiation
Issue number2
StatePublished - Feb 2014
Externally publishedYes


  • ERa
  • JAK2
  • PrlR
  • SOCS1
  • STAT1
  • breast cancer

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology


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