| First Author | Chan SR | Year | 2014 |
| Journal | Cell Death Differ | Volume | 21 |
| Issue | 2 | Pages | 234-46 |
| PubMed ID | 24037089 | Mgi Jnum | J:228994 |
| Mgi Id | MGI:5749933 | Doi | 10.1038/cdd.2013.116 |
| Citation | Chan SR, et al. (2014) Dysregulated STAT1-SOCS1 control of JAK2 promotes mammary luminal progenitor cell survival and drives ERalpha(+) tumorigenesis. Cell Death Differ 21(2):234-46 |
| abstractText | We previously reported that STAT1 expression is frequently abrogated in human estrogen receptor-alpha-positive (ERalpha(+)) breast cancers and mice lacking STAT1 spontaneously develop ERalpha(+) 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 ERalpha(+) 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 ERalpha(+) breast cancer in humans. |
