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Cell Death Differ. 2014 Feb;21(2):234-46. doi: 10.1038/cdd.2013.116. Epub 2013 Sep 13.

Dysregulated STAT1-SOCS1 control of JAK2 promotes mammary luminal progenitor cell survival and drives ERα(+) tumorigenesis.

Author information

1
Department of Pathology and Immunology, Washington University School of Medicine, 425S Euclid Avenue, St. Louis, MO 63110, USA.
2
1] Department of Pathology and Immunology, Washington University School of Medicine, 425S Euclid Avenue, St. Louis, MO 63110, USA [2] Department of Molecular and Translational Medicine, Section of Pathology, University of Brescia School of Medicine, Piazzale Spedali Civili 1, Brescia 25123, Italy.
3
Department of Molecular and Translational Medicine, Section of Pathology, University of Brescia School of Medicine, Piazzale Spedali Civili 1, Brescia 25123, Italy.
4
Oncology Drug Discovery, Research and Development, Bristol-Myers Squibb, Princeton, NJ 08543, USA.

Abstract

We previously reported that STAT1 expression is frequently abrogated in human estrogen receptor-α-positive (ERα(+)) breast cancers and mice lacking STAT1 spontaneously develop ERα(+) 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 ERα(+) 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 ERα(+) breast cancer in humans.

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PMID:
24037089
PMCID:
PMC3890946
DOI:
10.1038/cdd.2013.116
[Indexed for MEDLINE]
Free PMC Article
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