Background:
Metastasis at distant sites is the main cause of cancer deaths, particularly in women with breast cancer. The metastatic phenotype of cancer cells is controlled by signaling through the Ras-superfamily of small GTP-binding proteins including Rho GTPases.  Rho GTPases have been found to be overactivated or overexpressed in breast cancer.  Two p190 Rho GTPase-activating proteins (RhoGAPs), p190-A and p190-B, are expressed in the developing mammary gland (MG) in both the ducts and the stroma although p190-B is predominantly expressed in the Cap cells of the terminal end buds (TEBs). These two genes, which share 51% amino acid identity, map to different chromosomes suggesting they diverged early in evolution acquiring distinct functions. These proteins contain three distinct functional domains; a N-terminal GTPase domain that binds GTP/GDP similar to Rho and Ras, a middle FF domain (MD) which has been shown to interact with p120 RasGAP as well as transcription factor TFII-I suggestive of a scaffolding function for these proteins, and a C-terminal GAP domain responsible for inactivating GTP-bound Rho. Recent clinical data from ovarian cancer patients supports the hypothesis of differential functions for the two p190 RhoGAPs:  While increased expression of p190A correlates with an improved chance of survival, decreased p190B expression correlates with a reduced chance of survival.  Breast cancer clinical data show these same trends.

Homozygous deletion of p190-A or p190-B in mice results in perinatal lethality, although the phenotypes are markedly different. Transplants from p190-B null mice fail to grow, and histological evaluation reveals the mammary buds are smaller with disorganized mesenchyme. The p190-B+/- mice have delayed ductal morphogenesis between 4 and 5 weeks when the TEBs are the most proliferative. These phenotypes of the p190-B mice also suggest that there are distinct functions for p190-A and p190-B in mammary gland(MG) development.  One of the distinct roles of p190-B may be its ability to potentiate insulin-like growth factor (IGF) signaling making it a possible oncogene. Distinct functions of p190-A, a putative tumor suppressor, include induction during apoptosis in the prostate following castration and its ability to block the formation of PDGF-induced gliomas. Interestingly, preliminary co-immunoprecipitation results suggest that p190A and p190B interact in breast cancer cell lines and mouse breast cancer models, but not in normal mammary epithelium. Taken together; these data demonstrate the importance of elucidating the mechanisms through which these RhoGAPs function in MG development and breast cancer.
 
Objective/Hypothesis:
The aim of this study is to elucidate the roles of RhoGAP family members in mammary gland development and breast cancer progression. The central hypothesis is that p190-A and p190-B have divergent functions that cause them to act as opposing forces in breast cancer progression.  We suggest that p190-A may function as a tumor suppressor while p190-B may function as a proto-oncogene.

Heckman BM, Chakravarty G, Vargo-Gogola T, Gonzales-Rimbau M, Hadsell DL, Lee AV, Settleman J, Rosen JM.
Crosstalk between p190-B RhoGAP and IGF Signaling pathways is required for embryonic mammary bud development.
Dev. Bio. 2007; 309(1):137-149. [PDF]

Vargo-Gogola T, Heckman BM, Gunther EJ, Chodosh LA, Rosen JM.
P190-B RhoGAP overexpression disrupts ductal morphogenesis and induces hyperplastic lesions in the developing mammary gland.
Mol Endocrinol. 2006 June; 20(6): 1391-1405. [PDF]

Rice MC, Heckman BM, Liu Y, Kmiec EB.
Fluorescent detection and isolation of DNA variants using stabilized RecA-coated oligonucleotides.
Genome Res. 2004 Jan;14(1):116-25.