The cell death index as assessed by cleaved caspase 3 expression was less variable, and we found a higher cell death index in the erlotinib treated cohort than in controls, possibly indi cating that a fraction of the tumor cells still responded to EGFR inhibition while the majority of tumor cells were resistant. Finally, we examined whether Vandetanib clinical erlotinib had any effect on the growth of established tumors in this mouse model. Tumor metrics showed that once tumors were established, erlotinib did not shrink these tumors, and tumors grew similarly to the vehicle control treated tumors. The lack of efficacy of erlotinib on established tumors was seen Inhibitors,Modulators,Libraries in ER negative and ER positive tumors, further confirming that EGFR inhibition prevented the emergence of ER negative tumors but likely did not kill nascent ER negative emerged in erlotinib treated mice tended to be positive for ER and negative for EGFR and ALDH1.

Once tumors were established, their growth was not delayed by treatments with erlotinib, indicating that the majority of tumor cells are resistant to erlotinib treatment and grow independently of EGFR signaling. Discussion Haploinsufficiency phenotype of BRCA1 includes enhanced Inhibitors,Modulators,Libraries proliferation of MECs We previously found that that the nonmalignant MECs from BRCA1 mutation carriers contain a subpopulation of progenitor cells with significantly increased clonal and proliferative potential compared with normal con trols. Of these cells, 79% had not undergone loss of heterozygosity but had remained heterozygous for BRCA1, and these cells tended to differentiate into ER negative, EGFR positive colonies compared to controls.

Our observations con firm that even partial loss of BRCA1 leads to an increase a MECs clonal proliferation, lending further support to the concept that haploinsufficiency of BRCA1 with reduced protein levels of BRCA1 leads to a differentiation block coupled with enhanced prolifera Inhibitors,Modulators,Libraries tion of MECs. BRCA1 wt and BRCA1 haploinsufficient MECs depend on EGFR for proliferation MECs rely on EGFR activation for migration, prolifera tion and survival of mammary epithelial progenitor cells. However, the role that EGFR plays in either Inhibitors,Modulators,Libraries the initia tion or the maintenance of the malignant phenotype is largely unknown. Regardless of whether the progenitor cell population expanded through the loss of BRCA1 is defined by expression of ALDH1 or Epcam tumors.

In summary, we found that tumors that CD49, the progenitor cell population expanded in BRCA1 mutation carriers shows high EGFR expres sion relative to the control cells. Here we show that suppression of BRCA1 leads directly to an increase in EGFR expression with increased clonal growth of MECs, which can be entirely suppressed by Inhibitors,Modulators,Libraries the EGFR inhibitor promotion info erlotinib, suggesting that while loss of BRCA1 leads to an increase in EGFR activity, loss of BRCA1 does not convey growth factor independence.