Genetic Determinants of Inflammatory Breast Cancer

Primary inflammatory breast cancer IBC accounts for approximately 6 of new breast cancers annually. We hypothesized that a limited number of concordant genetic alterations give rise to the unique aggressive inflammatory phenotype of IBC. While working on the genetic determinants underlying the IBC phenotype, we found concordant and consistent alterations of two genes, RhoC GTPase and a novel IGF-binding protein IGF-BP, in patients with IBC. RhoC was overexpressed in 90 of IBC samples examined compared to 30 of stage matched non-IBC tumors. LIBC was lost in 80 of the IBC samples and only 20 of the non-IBC samples examined. Since RhoC and LIBC appear to act in concert in IBC, coupled to the preliminary evidence from other laboratories of genes from these families playing a role in pancreatic cancer another highly aggressive adenocarcinoma, they are excellent candidate genes to begin to probe the genetic basis of the aggressive phenotype in IBC. We hypothesize that the phenotype of IBC is due to alterations in expression of RhoC and TGF-BP early in tumorigenesis. We will elucidate the signaling pathway downstream from RhoC GTPase and attempt to determine what effect RhoC and LIBC have on cellular motility and invasion.