Interestingly, selleck chem inhibitor expression of Brk in HC11 or HMEC cells increased basal phospho p38 in serum Inhibitors,Modulators,Libraries starved cells, indicating that the presence of Brk is sufficient to promote p38 MAPK activation and survival of mammary epithelium. These data suggest that p38 phosphorylation induced by Brk expression in non transformed mammary epithelium could contribute to breast disease as either an early event or late event in tumorigenesis, thereby leading to a poor Inhibitors,Modulators,Libraries prognosis. Recent literature and our observations in HMEC and HC11 cell lines illustrate that Brk pro Inhibitors,Modulators,Libraries motes anchorage independent survival. Importantly, this has been shown to be a p38 MAPK dependent pheno type in Brk positive MDA MB 468 cells.

Taken together, these data suggest that Inhibitors,Modulators,Libraries Brk mediated p38 acti vation is likely a critical node for mammary epithelial cell pro survival and relevant to early oncogenic signal ing, p38 inhibitors may present an opportunity for ther apeutic intervention aimed at long term breast cancer prevention and or increased sensitivity to chemothera peutic agents. Conclusions This study characterizes the first mouse model of mam mary gland specific Brk PTK6 expression, and identifies Brk dependent Inhibitors,Modulators,Libraries signaling pathways associated with pro survival. Brk PTK6 expression in non transformed mammary epithelium causes delayed invo lution and promotes early tumorigenesis in aged mice, with signaling that recapitulates the same altered signal ing pathways present in human tumor biopsies. The identification of Brk dependent signaling events reveals potential therapeutic targets for Brk positive breast cancers.

The HER signaling pathway is one of the most studied and prominent drivers of human breast cancer progres sion. Aberrant overexpression, Enzastaurin FDA activation, and dimeriza tion of the individual members of the HER family comprised of EGFR HER1, HER2, HER3, and HER4 contribute both to aggressive tumor growth and poor patient prognosis. Amidst the complexity of the HER signaling network, HER2 has received a great deal of attention due to its frequent overexpression in tumors and its status as the preferred dimerization partner of the family. HER2 is amplified and or overexpressed in about 20% of human breast cancers and is independently associated with reduced disease free and overall survival. Two FDA approved drugs for the treatment of HER2 overexpressing tumors are the monoclonal antibody trastuzumab, and the EGFR HER2 tyrosine kinase inhi bitor lapatinib. Each drug is effective in inducing tumor regression in some patients with metastatic disease, but remissions are temporary since resistance commonly develops.