Journal
CELL DEATH AND DIFFERENTIATION
Volume 21, Issue 2, Pages 234-246Publisher
SPRINGERNATURE
DOI: 10.1038/cdd.2013.116
Keywords
breast cancer; STAT1; SOCS1; ER alpha; PrlR; JAK2
Categories
Funding
- National Cancer Institute
- Ludwig Institute for Cancer Research
- Fondazione Beretta
- Borsa di studio Prof Roberto Tosoni
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We previously reported that STAT1 expression is frequently abrogated in human estrogen receptor-alpha-positive (ER alpha(+)) breast cancers and mice lacking STAT1 spontaneously develop ER alpha(+) 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 alpha(+) 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 alpha(+) breast cancer in humans.
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