Breast cancer is not a single disease.  It is instead, a collection of diseases that display distinct histopathologies, genetic variability, and different prognostic outcomes.  My research focuses on understanding the functions of genes that control breast development and how altered regulation of these genes impacts the development and progression of breast cancer.  Advances in molecular medicine have allowed for tailoring of therapies to more effectively treat the different types of breast cancer.  Despite these advancements, the American Cancer Society estimates that 40,460 women will die from breast cancer this year and another 178,480 cases of invasive breast cancer will be newly diagnosed.  Thus, it is evident that a more complete understanding of the molecular basis of breast cancer is needed before we can improve existing therapies and develop new therapies to combat this complex disease. 

 My laboratory is particularly interested in understanding the role of a family of genes called the Rho family of small GTPases in mammary gland development and breast cancer.  Altered expression of Rho family genes has been detected in many types of cancer, including breast cancer.  Many of these genes are essential genes, which means that loss of gene function results in embryonic lethality in genetically engineered (transgenic) mice.  As a result, much of what we have learned about the function of the Rho family has come from studies using cultured cell lines.  These studies have yielded a wealth of information about the molecular functions of the Rho genes in a wide range of cellular processes such as cell movement, division, and survival.  However, how these genes function in the context of the complex environment of a developing animal and within specific tissues including the mammary gland, is not well understood. 

 My laboratory utilizes conditional transgenic mouse models to investigate how the loss and gain of Rho gene function affects mammary gland development and cancer.  We are currently investigating two different essential Rho family genes, p190-B Rho GTPase activating protein (GAP) and Cdc42.  In addition to these conditional mouse models, we use state-of-the-art technology in which mammary cells or clusters of mammary cells called organoids are isolated from the mouse mammary gland and propagated in a biological matrix as three-dimensional (3D) cultures.  These 3D culture conditions allow the mammary gland cells to undergo a morphogenic process that in comparison to cells grown on the surface of a plastic dish, more accurately recapitulates mammary gland development in the mouse.  Importantly, this culture system allows us to dissect complex molecular processes and cellular interactions that are difficult to investigate using mice.

P190-B RhoGAP is an essential gene that was identified in a screen for genes that are preferentially expressed in the terminal end buds (TEBs) of the developing mammary gland.  TEBs are the centers of proliferation and differentiation that drive outgrowth of the ductal epithelium to produce a mature mammary ductal tree.  Using p190-B deficient mice we have demonstrated that p190-B is essential for both embryonic and postnatal mammary gland development.  To investigate the role of p190-B during distinct stages of MG development, we have established tetracycline regulatable p190-B (Tet-O-p190-B) transgenic mice in which p190-B overexpression can be induced during each developmental and functional stage of the mammary gland including virgin development, pregnancy, lactation, and involution.  Using this model, we have demonstrated that p190-B plays a critical role in mediating stromal-epithelial interactions that are essential for TEB morphogenesis and formation of the mammary gland ductal tree.  Our current focus is to investigate the hypothesis that p190-B acts to integrate extracellular signals, and in turn, to regulate stromal-epithelial interactions that alter the microenvironment.  Both of these functions of p190-B are critical to drive morphogenesis and maintain tissue homeostasis in the developing mammary gland.  Furthermore, perturbation of p190-B signaling may facilitate breast cancer development by regulating both epithelial cell intrinsic behavior as well as the microenvironment.

 Vargo-Gogola T and Rosen JM, (2007) "Modeling breast cancer: one size does not fit all." Nature Reviews Cancer 7(9): 659-72.

 
Heckman BH, Chakravarty G, Vargo-Gogola T, Gonzales-Rimbau M, Hadsell D, Wysolmerski J, Rosen JM, (2007) "Cross-talk between the p190-B RhoGAP and IGF signaling pathways is required for embryonic mammary bud development." Developmental Biology 309(1): 137-49.

Lynch CC*, Vargo-Gogola T*, Martin MD, Linggi B, Fingleton B, Crawford HC, Carpenter G, Matrisian LM, (2007) "MMP-7 mediates mammary epithelial cell tumorigenesis through the ErbB4 receptor" Cancer Research 67(14): 6760-7.

Vargo-Gogola T, Heckman BH, Chodosh LA, Rosen JM, "P190-B RhoGAP overexpression disrupts ductal morphogenesis and induces hyperplastic lesions in the developing mammary gland." (2006) Molecular Endocrinology 20(6): 1391-1405.

Xian W, Schwertfeger KL, Vargo-Gogola T, Rosen JM, "Pleiotropic effects of FGFR1 on cell proliferation, survival and migration in a 3D mammary epithelial cell model." (2005) Journal of Cell Biology 171(4): 663-673.

Lynch CC, Hikosaka A, Acuff HB, Martin MD, Kawai N, Singh RK, Vargo-Gogola T, Betrup JL, Peterson TE, Fingleton B, Shirai T, Matrisan LM, Futakuchi M, "MMP-7 promotes prostate cancer-induced osteolysis via the solubilization of RANKL." (2005) Cancer Cell 7(5): 485-496. 

Vargo-Gogola T, Fingleton B, Crawford HC, Matrisian LM, "MMP-7 cleavage of Fas ligand releases a novel form of soluble Fas ligand." (2002) Archives of Biochemistry and Biophysics 408(2): 155-61.

Vargo-Gogola T, Fingleton B, Crawford HC, Matrisian LM, "Matrilysin (MMP-7) selects for apoptosis-resistant mammary cells in vivo." (2002) Cancer Research 62(19): 5559-63.

Fingleton B, Vargo-Gogola T, Crawford HC, Matrisian LM, "Matrilysin expression selects for cells with reduced sensitivity to apoptosis". (2001) Neoplasia 3(6): 459-468.

De Rocher EJ, Vargo-Gogola T, Diehn SH, Green PJ, "Direct evidence for rapid degradation of Bacillus thuringiensis toxin mRNA as a cause of poor expression in plants." (1998) Plant Physiology 117:1445-1461.