We performed sequencing analyses on a subset of the UNC breast tumors analyzed by microarray for EGFR mutations
In both data sets, the high expression of MEK2 and HRAS was associ ated with Cluster 1, screening library while the high expression of many other genes correlated with Clusters 2 and 3. of note was the high expression of the KRAS amplicon, HRAS, NRAS, and MEK1 with both Clusters 2 and 3, and the high expression of EGFR selleck chemicals llc with only Cluster 2. The association of different genes with the three EGFR associated signa tures is likely reflective of the complexity of signaling in this pathway across breast cancers and suggests possible driving molecular PKC signaling mechanisms for each EGFR associated profile. One of the few genes whose high expression was significantly corre lated with this subtype was the HER4 receptor. high expression of HER4 and average expression of two of its ligands was observed in this tumor subtype that typically shows low grade, slow growth, and an ER rich expression signature. The luminal B tumors showed moderate to high expres sion of the EGFR associated profiles, high HRAS expres sion, and potentially high MEK2 expression. The EGFR HER2 pathway has often been implicated as a potential mechanism for tamoxifen resistance in ER patients. We determined that the high expres sion of the EGFR associated profiles was able to predict outcome differences in ER and tamoxifen treated patients in both the UNC and NKI data sets. however, it should be noted that the expression of these clusters in ER patients closely parallels the dis tinction of luminal A versus luminal B. These results sug gest that part of the luminal A versus luminal B distinction is due to the activation of the EGFRHER2 pathway in luminal B tumors. In support of this hypothesis, ninety six percent of the luminal B tumors showed high expres sion of at least one of the three EGFR associated clusters, whereas only 24% of luminal A tumors had high expres sion of at least one. Our results are also consistent with the hypothesis of the non genomic effects of ER to activate the HER pathway, where membrane bound ER complexes with EGFR andor HER2 to cause activation of the RAS MEK and p38 pathways, and suggests that these ER non genomic effects are occurring in luminal B tumors. Response to EGFR inhibitors in ER positive tumors have been mixed with some indicating a benefit, while others found no benefit. A hypothesis that could be tested is that the high expression of one or more of the EGFR associated gene sets in ER tumors might correlate with responsebenefit to EGFR inhibitors. The HER2ER tumors, as expected, showed statistically high expression of HER2 and were also associated with high HRAS and MEK1MEK2. High AKT1 lev els were also associated with this tumor subtype, which has been previously identified. The basal like subtype showed the high expression of each of the three EGFR associated profiles. ninety one percent of the basal like tumors had high expression of at least one of the signatures with 58% of the tumors having high expression of all three. High expression of many of the genes in the EGFR RAS MEK pathway were also signifi cantly correlated with the basal like subtype including EGFR, TGF, MEK1, MEK2, AKT3, CRYAB, NRAS and the KRAS amplicon signature.