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Defining the Role of the Ras Family RERG Protein in Breast Cancer
Background: We identified RERG (Ras-related and Estrogen-Regulated Growth inhibitor) in microarray analyses for genes whose expression was decreased or loss in a significant percentage of primary human breast tumors that showed poor clinical prognosis. RERG expression correlated exclusively with estrogen receptor expression in human breast cancer patient tumors and cell lines. Surprisingly, RERG encodes a protein highly related in sequence (~50% amino acid identity) and biochemistry (GTPase) to the Ras oncoprotein. Ras genes are mutated in human cancers and encode constitutively activated proteins that promote uncontrolled growth and tumor invasion. In contrast, it is the loss of expression in estrogen receptor negative breast cancers, rather than activation, of RERG that promotes oncogenesis. Forced overexpression of RERG expression in breast tumor cells caused inhibition of colony formation in soft agar and tumor formation in nude mice, supporting a functional role for RERG loss in breast cancer development. Thus, while Ras functions as an oncogene, RERG functions as a tumor suppressor gene. How the loss of RERG expression promotes breast cancer development and how RERG functions as a tumor suppressor have not been determined. Loss of RERG expression may be a useful diagnostic marker for breast cancer progression. Pharmacologic restoration of the RERG function that impairs breast cancer growth may be a promising approach for breast cancer treatment.
Objective/Hypothesis: The objective of our proposal is to determine the specific contribution of the loss of RERG expression to breast cancer growth and to delineate the mechanisms by which RERG causes growth inhibition of RERG-deficient breast tumor cells. One hypothesis is that RERG can interact selectively with Ras effectors involved in growth inhibition (Nore1, RASSF1). Alternatively, RERG interacts with and utilizes unique effectors that regulate signaling pathways that lead to growth inhibition. Our studies will distinguish between these two mechanisms.
Specific Aims: We propose aims (1) to determine the structural and biochemical properties important for RERG suppression of breast cancer growth, (2) to define the effector targets that function downstream of RERG that are involved in growth inhibition, and (3) to determine if RERG suppresses growth by deregulation of cell cycle progression and increased apoptosis.
Study Design: First, a variety of mutants of RERG, based on known functional mutants of Ras, will be evaluated to determine what structural and biochemical properties of RERG are important for RERG inhibition of breast carcinoma cell proliferation. Second, whether RERG can bind to effectors of Ras that promote growth inhibition, or alternatively, bind to unique effectors, will be determined. Third, studies will be done to determine if RERG promotes growth inhibition by activation of the Rb tumor suppressor pathway to cause cell cycle inhibition and if RERG may also promote decreased cell survival.
Potential Outcomes and Benefits of Research: Since RERG expression is lost in estrogen receptor negative breast cancers, RERG may be a useful diagnostic marker for advanced breast cancers. The goal of our study will be to determine the signaling mechanisms by which RERG inhibit the growth of breast carcinoma cells. This may define directions for the development of pharmacologic approaches that “reactivate” RERG growth inhibitory activity in advanced breast cancers, and establish a novel anti-breast cancer treatment strategy for estrogen receptor-negative breast cancers.
It is now clear that breast cancer is a genetic disease where “good genes have gone bad” and arises as a consequence of mutations in genes that control normal growth proliferation and cell survival. Research has already defined important genetic events involved in breast cancer development, for example, the overexpression and activation of the HER2 oncogene and the loss of function of the BRCA1 and BRCA2 tumor suppressor genes. The discovery that these genes are aberrantly expressed or mutated in breast cancers has led to novel anti-breast cancer drugs or genetic screens, respectively, for the treatment of breast cancer. While we have made significant strides in defining key genetic events involved in breast cancer develop, much remains to be discovered regarding other genetic alterations that contribute to breast cancer development. One important genetic change for many cancers, but not breast cancer, is the mutational activation of the Ras oncogene. However, recent studies determined that a Ras-related protein, called RERG, may be important for breast cancer development. Loss of RERG expression correlated with the loss of estrogen receptor expression in breast cancer patient tumors and cell lines. RERG expression for 78 breast tumors was a statistically significant predictor of patient outcome. What is surprising is that, although Ras and RERG are very similar proteins, they have opposite roles in cancer development. Whereas Ras becomes activated in human cancers and promotes uncontrolled growth, RERG expression is lost in estrogen receptor negative breast cancers and displays the growth inhibitory activities of a tumor suppressor in breast cancer cells. Is the loss of RERG really important to allow breast cancers to progress to a more invasive and malignant stage? If so, how does RERG work normally to prevent breast cancer advancement? These are two of the key questions that we will answer in our research studies. Our studies may help validate the loss of RERG expression as an important diagnostic marker for advanced breast cancers. An important goal of our proposal will be to determine how RERG prevents breast cancer cell growth. We can then take advantage of this information to design new drugs that mimic the actions of RERG, to “reactivate” RERG in RERG-deficient breast cancers and prevent their growth and advancement. In summary, understanding the function of RERG in normal and neoplastic breast cells will provide further understanding of the basic biology of breast cells and may establish RERG as an important diagnostic marker or target for drug discovery for breast cancer treatment.