Indeed, differences between the kinase inhibitor Ceritinib isoforms may help to reconcile contradictory effects reported for AP 2a, in particular in breast tumour studies, and also may explain the partially overlapping yet distinct roles observed for AP 2a, b and g during development. Primary prevention of breast cancer has traditionally centered on estrogen receptor blockade, largely because the vast majority of breast cancers express ER and because ER antagonists are both easily administered and well tolerated. However, ER antagonists do not pre vent the most aggressive form of breast cancer, tumors that are ER and progesterone negative. These tumors account for 15% to 20% of all breast cancers, occur with disproportionately Inhibitors,Modulators,Libraries high frequency in African Americans and carry the worst prognosis.

The sub group of Inhibitors,Modulators,Libraries women who are at highest risk for ER and PR negative breast cancers are women who carry a germline mutation in BRCA1. These women typically develop triple negative breast cancers, which are defined by the absence of ER, PR and Her2 expres sion and are thought to be caused by genetic instability that results from a germline mutation in BRCA1. Though nominally classified as a diagnosis of exclu Inhibitors,Modulators,Libraries sion, TNBC tumors frequently overexpress epidermal growth factor recep tor, whereas only a minority of ER positive breast cancers overexpress EGFR. The high frequency of EGFR expression in TNBCs suggests that loss of BRCA1 may be coupled, either directly Inhibitors,Modulators,Libraries or indirectly, with EGFR overexpression in breast cancer. This connection is further supported by the finding that sporadic TNBCs frequently exhibit both epigenetic silencing of BRCA1 and overexpression of EGFR.

However, how TNBCs enrich for tumor cells with high EGFR expression is unknown. Previously, we examined the Inhibitors,Modulators,Libraries proliferation and differ entiation properties of BRCA1 mutant primary human MECs and found a disproportionate frac tion of progenitor cells in BRCA1 mutation carriers with concomitant EGFR overexpression and absence of ERa. Here we report that inhibition of BRCA1 in MECs leads to the upregulation of EGFR and the expansion of an aldehyde dehydrogenase 1 positive mammary epithelial progenitor cell population. We show that these MECs are exquisitely sensitive to EGFR inhibition with erlotinib and that EGFR inhibition in vivo could prevent the emergence of TNBCs.

Materials and methods Reagents Phycoerythrin conjugated mouse anti EGFR anti selleck chemicals body, PE conjugated mouse immuno globulin G2b isotype control antibody were obtained from BD Biosciences, San Diego, CA, USA, and QuantiBrite beads were obtained from BD Biosciences, San Jose, CA, USA. The ALDEFLUOR assay kit was purchased from STEMCELL Technologies, Durham, NC, USA. Rhodamine EGF was purchased from Invitrogen, Carlsbad, CA, USA. For immunofluorescence analysis, we used a mouse anti EGFR antibody obtained from BD Biosciences, San Diego, CA, USA.