Resveratrol in breast cancer cell survival or apoptosis

描述(由申请人提供)：通过雌激素受体(ER)和表皮生长因子受体(EGFR)传递的信号对正常乳腺发育以及乳腺癌的发生和发展至关重要。最近关于雌激素快速作用的研究，包括我们的初步和已发表的数据，表明雌激素信号是复杂的，可能涉及促进与EGFR信号相互作用的非基因组途径。白藜芦醇是一种由红酒和葡萄皮组成的雌激素样类固醇化合物，被认为与癌症预防有关。在ERα(+)的乳腺癌细胞中，白藜芦醇已被证明可以促进生长停滞和凋亡。我们已发表的和初步的数据表明，ER异构体状态依赖的白藜芦醇通过调节原癌基因Akt的活性而影响乳腺癌细胞的存活。该应用的目的是阐明ER和EGFR亚型在白藜芦醇介导的乳腺癌细胞增殖或停滞中的作用。这一应用的中心假设是，白藜芦醇对乳腺癌细胞周期进程或停滞的信号依赖于ER亚型状态。这项拟议研究的基本原理是，阐明白藜芦醇作为细胞死亡或存活和增殖的调节器的作用，对于确定白藜芦醇作为乳腺癌预防和乳腺癌促进剂的双重作用非常重要。我们验证这一假说的实验方法是分析ER阴性的乳腺癌细胞株的相对细胞周期进程，该细胞株仅异位表达载体ERα、ERβ或两者都有。我们的第一个特定目标是确定在白藜芦醇治疗后，在存在或不存在ER或EGFR特异性抑制剂的情况下，ERα、β或EGFR的激活状态。我们的第二个特定目标是在相同的细胞系中研究调节ER或EGFR活性对白藜芦醇介导的细胞周期进程的影响。这将通过分析白藜芦醇在存在或不存在ER或EGFR抑制剂的情况下对细胞周期进程的影响来实现。这项及时的研究有望填补我们目前对白藜芦醇作为预防乳腺癌高危女性和幸存者的有效性的认识的相当大的空白。

DESCRIPTION (provided by applicant): Signaling via estrogen receptors (ER) and epidermal growth factor receptors (EGFR) are critical for normal mammary gland development as well as breast cancer initiation and progression. Recent studies on rapid effects of estrogen, including our preliminary and published data, indicate that estrogen signaling is complex and may involve non-genomic pathways that facilitate cross-talk with EGFR signaling. The estrogen-like steroidal compound of red wine and grape skins, resveratrol, has been linked to cancer prevention. In ER alpha (+) breast cancer cells, resveratrol has been shown to promote growth arrest and apoptosis. Our published and preliminary data demonstrate ER isoform status-dependent resveratrol effects on breast cancer cell survival by modulation of the activity of the protooncogene Akt. The objective of this application is to elucidate the role of ER and EGFR isoforms on resveratrol-mediated breast cancer cell proliferation or arrest. The central hypothesis of this application is that signaling for breast cancer cell cycle progression or arrest by resveratrol is dependent on ER isoform status. The rationale for the proposed research is that elucidation of the role of resveratrol as a modulator of cell death or survival and proliferation is important for ascertaining a dual role for resveratrol as a breast cancer preventive and a promoter of established breast cancer. Our experimental approach for testing this hypothesis is to analyze relative cell cycle progression in a ER negative breast cancer cell line that ectopically express vector alone, ER alpha, ER beta, or both ER isoforms. Our first specific aim is to determine the activation status of ER alpha, beta, or EGFR following resveratrol treatment in the presence or absence of ER or EGFR specific inhibitors. Our second specific aim is to investigate the effect of modulating ER or EGFR activity on resveratrol-mediated cell cycle progression in the same range of cell lines. This will be achieved by analysis of the effect of resveratrol on cell cycle progression in the presence or absence of inhibitors to ER or EGFR. This timely research promises to fill the considerable gap in our current knowledge concerning the efficacy of resveratrol as a preventive for both women at high risk and survivors of breast cancer.