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Research Grants Awarded
CAV-1 in Estrogen-Dependent Breast Cancer
The long-term objective of this proposal is to understand the role of caveolae and caveolin-1 in breast cancer onset and progresssion. Caveolae are "little caves" at the surface of cells that function both in vesicular trafficking and signal transduction. Caveolin-1 is the principal oligomeric structural protein of caveolae membranes that are found in most cell types. Recently, we have mapped the human caveolin-1 gene (CAV-1) to the D7S522 locus/ 7q31.1, a suspected tumor suppressor locus that is deleted in many forms of human cancer. In addition, up to 16 % of human breast cancers harbor a dominant-negative mutation, P132L, in the CAV-1 gene. The aim of this proposal is to test the hypothesis that caveolin-1 expression is important for negatively regulating breast cancer onset and progression. In order to test this hypothesis, we will employ a variety of complementary in vivo approaches, such as the use of a caveolin-1 (-/-) null mouse animal model-generated in the mentor/sponsor's laboratory-which spontaneously develops severe mammary epithelial cell hyperplasia (a premalignant lesion). The overall goal of this proposal is to determine the role of the ER-alpha in Cav-1-mediated mammary epithelial cell function, with a focus on the development of tamoxifen resistance. Estradiol plays a key role in human breast cancer onset and progression. We found that somatic mutations of Cav-1 occur in >30% of ER-alpha positive, but not ER-alpha negative human breast tumors. Using Cav1-/- mice we have shown Cav-1 normally represses ER-alpha expression and activity in the mammary gland. We will determine the functional significance of Cav-1-mediated ER-alpha repression in vivo using the mammary glands of Cav1-/- mice -- treated with estrogen receptor agonists (estradiol) and antagonists (tamoxifen), or left untreated. Exposure to estrogen is a critical risk factor for the development of human breast cancers. In support of this notion, early menarche and late menopause are associated with an increased breast cancer risk. Tamoxifen resistance occurs in up to 40% ER-alpha positive patients. As such, understanding the molecular mechanisms underlying tamoxifen resistance is highly clinically significant.
Human breast cancer is a clinically heterogeneous disease, and can be provisionally divided into two prognostic categories based on the expression of the estrogen receptor (ER-alpha). Roughly, 70 % of breast cancers are ER-alpha positive, and this is generally considered a favorable prognostic factor-as these patients can be treated with tamoxifen-an estrogen receptor antagonist. However, it is now well-appreciated that up to 40% of ER-alpha positive patients show tamoxifen-resistance. The mechanism(s) underlying this important clinical phenomenon remain largely unknown. In addition, it is not known how estrogen receptor becomes upregulated in pre-malignant lesions (mammary epithelial cell hyperplasia) and frank breast cancers. To address these issues, we have developed a new mouse model to study the role of ER-alpha in breast cancer onset and progression. We will also use this model to study the onset and dynamics of tamoxifen resistance. This is an important question, as up to 40% of ER-positive breast cancer patients show tamoxifen resistance, leading to a poor prognosis (recurrent and metastatic disease).