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    Wrch1: A Novel Rho GTPase in Breast Cancer Development

    Scientific Abstract:
    Wrch1: A Novel Rho GTPase in Breast Cancer Development Background: The Rho family of small GTPases (23 human members) is a major branch of the Ras superfamily. The best characterized members are Rac1, Cdc42, and RhoA, and these proteins have been shown to function as signaling proteins that regulate actin organization, cell cycle progression, and gene expression. There is considerable evidence for the involvement of aberrant Rho GTPase function in breast cancer development. Overexpression of RhoC has been associated with inflammatory breast carcinoma development. Aberrant activation of Rac1 and Cdc42 promotes breast cancer cell invasion. Overexpression of a novel splice variant of Rac1, Rac1b, is seen in breast cancers. RhoA, RhoB, Rac1 and CDC42 protein expression is enhanced in breast tumor, but not normal, tissues. Recent studies have implicated a novel Rho GTPase, Wrch1, in breast cancer development. Firstly, Wrch1 gene expression is upregulated by Wnt1 transformation of mammary epithelial cells, and Wrch1 activation exactly phenocopied Wnt-1 transformation. Secondly, Wrch1 expression is downregulated by estrogen treatment of MCF-7 breast carcinoma cells. However, a clear involvement of Wrch1 in breast cancer remains to be determined. With the increasing evidence that aberrant Rho GTPase function promotes human tumor cell invasion and metastasis, we propose to evaluate the role of Wrch1 in breast cancer development. Hypothesis: The aberrant expression and activation of Wrch1 contributes to the uncontrolled growth, development and invasion of breast cancer cells. Recently developed farnesyl- or geranylgeranyltransferase inhibitors may inhibit Wrch1 function and be useful for the treatment of breast cancers with aberrant Wrch1 expression and activation. Specific Aims: Specific Aim 1 — To determine the ability of Wrch1 activation to cause human mammary epithelial cell growth transformation and invasion. Specific Aim 2 — To determine the ability of prenyltransferase inhibitors (FTI and GGTI) to block Wrch1 mediated transformation. Study Design: Model human mammary epithelial cell systems will be used to determine the signaling mechanisms by which Wrch1 promotes transformation and tumor cell invasion. Finally, we will determine if Wrch activity can be blocked by recently developed pharmacologic inhibitors of farnesyltransferases or geranylgeranyltransferases, using cell-based models of transformation and invasion. Since Wrch1 is most similar to Cdc42 in sequence and function, Cdc42 will be used as a positive control for these studies. Potential Outcomes and Benefits of the Research: From our studies, we will gain an important understanding of the role and mechanism of Wrch1 in breast epithelial cell oncogenesis. Aberrant Wrch1 expression and activation may serve as an important marker for advanced breast cancers and define breast cancer patients for treatment with prenyltransferase inhibitors.

    Lay Abstract:
    Wrch1: A Novel Rho GTPase in Breast Cancer Development The importance of aberrant cell signal transduction in breast cancer development is well established. For example, overexpression of the HER2 receptor is associated with advanced and invasive breast cancers. Inhibition of HER2 signaling by Herceptin is an important therapeutic approach for breast cancer treatment. Recently, a new class of signaling proteins, the Rho family proteins, have been linked to breast cancer development. Rho proteins normally act to control cell growth and cell shape, yet there is considerable evidence that the aberrant activation of multiple Rho family proteins (e.g., RhoA, RhoC, Rac1, Rac1b, CDC42) can promote breast cancer development. Rho family proteins are related to Ras proteins, and mutated Ras proteins are found in 30% of human cancers. Recently, a novel Rho family protein, called Wrch1, was identified and current evidence suggests a role for Wrch1 in breast cancer development. Firstly, the transformation of mammary epithelial cells by the Wnt1 signaling protein is associated with increased expression of Wrch1. Wnt1 was identified originally as a protein that caused mammary tumors in mice. Wrch1 activation alone can both mimic the actions of Wnt1 and cause mammary cell transformation. Secondly, estrogen stimulation of estrogen receptor positive, noninvasive, breast cancer cells causes a loss of Wrch1 expression. Since estrogen receptor expression is associated with less invasive breast cancers, perhaps the ability to lose Wrch1 expression prevents these cancers from metastatic growth and spreading. Apart from these observations, there has been limited research to critically assess the importance of Wrch1 in breast cancer development. Since other Rho proteins have established roles in breast cancer development, it is highly likely that Wrch1 will also be important in breast cancer. We propose studies to evaluate how Wrch1 may be activated in breast cancers and whether Wrch1 activation contributes to breast cancer growth and invasion. Finally, a class of drugs have been developed that block the function of other Rho proteins. These include farnesyltransferase (which are under clinical trial evaluation) and geranylgeranyltransferaseI (which show anti-tumor activity in preclinical mouse models) inhibitors. We will determine if these drugs block the ability of Wrch1 to promote breast cancer development. In summary, the goal of our studies will be to critically evaluate whether aberrant Wrch1 expression will serve as a useful diagnostic marker for advanced breast cancers and whether inhibition of Wrch1 function will be useful for breast cancer treatment.