We previously reported that STAT1 expression is frequently abrogated in human estrogen receptor-a-positive (ERa þ ) breast cancers and mice lacking STAT1 spontaneously develop ERa þ 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 þ luminal progenitor cells and development of ERa þ mammary tumors. A failure to upregulate SOCS1, a STAT1-induced inhibitor of JAK2, leads to unopposed oncogenic PrlR signaling in STAT1 À / À 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 ERa þ breast cancer in humans. Cell Death and Differentiation (2014) 21, 234-246; doi:10.1038/cdd.2013.116; published online 13 September 2013Estrogen receptor-a-positive (ERa þ ) breast cancer, the most commonly diagnosed subtype of breast malignancy in women, is routinely treated with combinations of endocrine therapies and radiation or chemotherapy. Nevertheless, half of the patients do not benefit from these treatments because of intrinsic or acquired resistance. 1 Therefore, alternative therapeutic targets in ERa þ breast cancer need to be developed.Work by others has revealed a mammary tumor-promoting effect of prolactin receptor (PrlR) signaling in humans and mice. A meta-analysis of epidemiological data concluded that women in the top quartile for serum prolactin (Prl) concentration have a 60% increased risk of developing ERa þ , but not ERa À , breast cancer, compared with those in the bottom quartile. 2 Consistent with these findings, upregulated PrlR expression and constitutive activation of STAT3 and STAT5 is frequently found in human ERa þ breast cancers. [3][4][5][6]

We report the characterization of BMS-911543, a potent and selective small-molecule inhibitor of the Janus kinase (JAK) family member, JAK2. Functionally, BMS-911543 displayed potent anti-proliferative and pharmacodynamic (PD) effects in cell lines dependent upon JAK2 signaling, and had little activity in cell types dependent upon other pathways, such as JAK1 and JAK3. BMS-911543 also displayed anti-proliferative responses in colony growth assays using primary progenitor cells isolated from patients with JAK2 V617F -positive myeloproliferative neoplasms (MPNs). Similar to these in vitro observations, BMS-911543 was also highly active in in vivo models of JAK2 signaling, with sustained pathway suppression being observed after a single oral dose. At low dose levels active in JAK2-dependent PD models, no effects were observed in an in vivo model of immunosuppression monitoring antigen-induced IgG and IgM production. Expression profiling of JAK2 V617F -expressing cells treated with diverse JAK2 inhibitors revealed a shared set of transcriptional changes underlying pharmacological effects of JAK2 inhibition, including many STAT1-regulated genes and STAT1 itself. Collectively, our results highlight BMS-911543 as a functionally selective JAK2 inhibitor and support the therapeutic rationale for its further characterization in patients with MPN or in other disorders characterized by constitutively active JAK2 signaling.

Background: Surfactant protein A stimulates macrophage chemotaxis. Results: SPA interaction with TLR2 stimulates JNK-and ERK-dependent TGF␤ production, which in turn stimulates RHAMM-and hyaluronan-dependent macrophage chemotaxis. Conclusion: SPA activates a novel and specific pathway to stimulate macrophage chemotaxis. Significance: Uncovering the mechanisms that regulate innate immunity in the lung is crucial for understanding the responses to infection and injury.