Mechanisms for Gender Differences in Lung Adenocarcinoma: Estrogen Action in Lung Adenocarcinoma

  • Kim, Kyung (PI)

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The higher frequency of lung cancer in women than in men smokers implicates gender-dependent factors lung cancer etiology. Estrogens are the female sex hormones that playa critical role in breast and endometrial cancers, but little is known about estrogen action in lung cancer. Indeed, up until 1997, lung was not considered to be a target of estrogen. Estrogens work by binding to a protein called estrogen receptor (ER). In turn, ER binds to DNA and stimulates production of messenger molecules that make cells divide. There are two types of ERs in cells: ERa and ERr3. Although a few people have examined ERa and ERr3expression in human lung cancer, but the results are mixed. We took a different approach and studied not only ER expression, but if estrogen would stimulate human lung adenocarcinoma cells to divide. Our results were that estrogen caused lung cancer cells from women, but not men, to grow and that the drug tamoxifen, which is used clinically to treat breast cancer, blocked estrogen-stimulated lung cancer cell growth! The present set of experiments is a follow-up study to determine how estrogens cause lung adenocarcinoma cells to grow and how antiestrogens block this growth. We have 4 overall Specific Aims which are goals of the proposed experiments: 1) Determine if chimeric estrogen receptors (ER) ERa-VP16 and ERr3-VP16 activate estrogen-response element (ERE)-driven luciferase activity in transfected lung adenocarcinoma cells. 2) Identify estrogen-regulated genes in lung adenocarcinoma cells from females and males. 3) Determine the efficacy of Er and ICI182,780- Protac (_Pr_oteolysis_Targeting Chimeric) molecules in inhibiting lung adenocarcinoma cell proliferation and estrogen target gene expression. 4) Determine if E2, sodium arsenite (NaAs02), and cadmium chloride (CdCI2) rapidly activate non-genomic/membraneinitiated ER activation of MAPK activity in lung adenocarcinoma cells. Other investigators have demonstrated that cadmium and arsenite act like estrogens in female reproductive tissues, but no one has evaluated if they have estrogenic activity in lung. If they do, this could be a reason why women, smokers or non-smokers have twice the lung adenocarcinoma compared to male smokers. It is our hope that the successful completion of these experiments will define the molecular mechanisms of estrogen, cadmium, and arsenite action in lung adenocarcinoma and could provide rationale for clinical trials for antiestrogens to treat patients with lung adenocarcinoma. University of Louisville 9/23/05
Effective start/end date9/1/078/31/08


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