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The Role of Caveolin-1 in Breast Cancer Susceptibility
Background: Caveolin-1 (Cav-1) is a tumor suppressor that is down regulated in primary breast tumors but the mechanisms that regulate Cav-1 expression in the normal breast are unknown. We have shown that high levels of E2 exposure in utero increase whereas E2 exposure during prepuberty decreases susceptibility to breast cancer in rats. We have also found that Cav-1 is down regulated in the epithelial mammary gland tissue from rats exposed to E2 in utero but up regulated in rats exposed to E2 during prepuberty compared to control. Thus, Cav-1 expression/function in the breast is related to susceptibility to malignant transformation. Consistent with these changes in Cav-1 expression and its role as a scaffolding protein, in utero E2 exposure increased expression of activated Akt and Src while prepubertal E2 exposure reduced them. Phosphorylation on tyrosine 14 (pY14) alters binding capacity of Cav-1 to signaling molecules but its relevance in breast cancer is unknown. We have found that pY14 is required for Cav-1-mediated E2 responsiveness in breast cancer cells. Objective/Hypothesis: Our objectives are (1) to verify the requirement of Cav-1 in regulating susceptibility to breast cancer in response to age at E2 exposure and (2) to characterize the role of Cav-1 tyrosine phosphorylation in E2 responsiveness in breast cancer cells. Our hypothesis is that the age at E2 exposure controls Cav-1 expression in determining breast cancer risk, and that Cav-1 tyrosine phosphorylation is required for the regulation of its target molecules. Specific Aims/Study Design: In Aim 1, wild-type and Cav-1 knockout mice will be exposed to E2 in utero and during pre-puberty to verify regulation of Cav-1 by age at E2 exposure. In Aim 2, MCF-7/LCC1 cancer epithelial cells that stably express wild-type or phosphorylation-deficient mutant (Y14F) Cav-1 will be used to identify Cav-1 target genes that control responsiveness to E2 through microarray analyses. Specific pharmacological inhibitors of ERalpha and Cav-1 will be used to determine the signaling mechanism of Cav-1-pY14 in cell proliferation and apoptosis. Outcomes/Benefits: Our studies will uncover the role of Cav-1 in relation to age or developmental stage of the mammary gland at the time of E2 exposure that modifies later breast cancer risk. Both in vivo and in vitro studies will reveal how Cav-1 regulates E2-mediated key determinants of breast cancer susceptibility, i.e., cell proliferation and differentiation.
Background: Caveolin-1 (Cav-1) is a tumor suppressor that is decreased in primary breast tumors. Cav-1 is also a regulatory protein in estrogen signaling. Timing of estradiol (E2, active form of estrogen in the body) exposure is linked to breast cancer risk. We have shown that high levels of E2 exposure before birth increases whereas similar E2 exposure during prepuberty decreases breast cancer risk in rats. We have also found that Cav-1 expression is reduced in rats exposed to E2 before birth but increased in rats exposed to E2 during prepuberty compared to untreated rats. These results suggest a correlation between Cav-1 and breast cancer susceptibility. Cav-1 is regulated by a process called tyrosine phosphorylation (a molecular on/off switch mechanism by which signaling proteins are regulated in a cell) but its role in breast cancer is unknown. Our studies in human breast cancer cells show that Cav-1 tyrosine phosphorylation is essential in E2 responsiveness . Objectives/Hypothesis: Our objectives are (1) to verify the requirement of Cav-1 in regulating susceptibility to breast cancer in response to E2 and (2) to characterize the role of Cav-1 tyrosine phosphorylation in E2 responsiveness in breast cancer cells. Our hypothesis is that the age at E2 exposure determines breast cancer risk by controling expression/function of Cav-1, and that Cav-1 tyrosine phosphorylation is required for the regulation of its target molecules. Specific Aims/Study Design: In Aim 1, we will expose normal and Cav-1 knockout mice (that do not express the cav-1 gene) to E2 before birth or during prepuberty to determine the requirement of Cav-1 in regulation of cell proliferation and cell death. In Aim 2, breast cancer cells (MCF-7/LCC1) that have been engineered to express either normal Cav-1 or a mutant Cav-1 (cannot undergo tyrosine phosphorylation) will be used for microarray analyses and biochemical studies with inhibitory drugs to identify Cav-1 targets. Outcome/Benefits: Our studies will uncover how age at E2 exposure regulates Cav-1 function to determine breast cancer risk and how Cav-1 tyrosine phosphorylation controls E2 responsiveness in breast cancer. Given the close relationship between Cav-1 and E2 signaling, results from our work will facilitate the development of novel therapeutic agents and preventive measures for breast cancer.