Abstract
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 language | English |
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Pages (from-to) | 234-246 |
Number of pages | 13 |
Journal | Cell Death and Differentiation |
Volume | 21 |
Issue number | 2 |
DOIs | |
State | Published - Feb 2014 |
Keywords
- ERa
- JAK2
- PrlR
- SOCS1
- STAT1
- breast cancer