Mechanistic Links Between Changing Estrogen Profiles, Inflammation and the Increased Risk and Metastasis of Breast Cancer in Obese Women

肥胖女性雌激素水平变化、炎症与乳腺癌风险增加和转移之间的机制联系

• 批准号: 10197485
• 负责人: JOYCE MARIE SLINGERLAND
• 金额: $ 27.73万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-07 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10197485
• 关键词: Adipocytes; Adipose tissue; Adverse effects; Affect; Alzheimer' s Disease; Anabolism; Androstenedione; Aromatase; Aromatase Inhibition; Aromatase Inhibitors; Binding; Biological Assay; Body mass index; Breast; Breast Cancer Cell; Breast Cancer Patient; Breast Cancer Prevention; Breast Cancer Risk Factor; Breast cancer metastasis; CCL2 gene; Cardiovascular Diseases; Cell Communication; Chronic; Coculture Techniques; Cytokine Gene; Data; Development; Enzyme Tests; Enzymes; Equilibrium; Estradiol; Estrogen receptor positive; Estrogens; Estrone; Fatty acid glycerol esters; Gene Expression; Grant; Growth; Heart Diseases; Hormone replacement therapy; Hormones; Human; IL6 gene; IL8 gene; Implant; In Vitro; Incidence; Inflammation; Inflammation Mediators; Inflammatory; Invaded; Knock-out; Knockout Mice; Lead; Letrozole; Link; MCF7 cell; Malignant Neoplasms; Mammary gland; Mediating; Menopause; Mus; Neoplasm Metastasis; Neurodegenerative Disorders; Nuclear; Obesity; Outcome; Overweight; Pathway interactions; Post-Menopausal Hormone Replacement Therapy; Postmenopause; Prevention; Production; Risk; Role; Serum; Site; Testing; Therapeutic; Thinness; Tissues; Tumor Tissue; Woman; cancer cell; cancer initiation; cancer stem cell; cancer therapy; cell type; chromatin immunoprecipitation; cytokine; design; estrogenic; falls; gene induction; genetic corepressor; in vivo; inhibitor/antagonist; malignant breast neoplasm; new therapeutic target; outcome forecast; overexpression; p65; prevent; promoter; self-renewal; stem cells; targeted treatment; therapy resistant; transcription factor; tumor; tumor initiation; tumor progression; tumorigenesis

Project Summary Obesity increases the risk and adverse prognosis of postmenopausal estrogen receptor-positive (ER+) breast cancer. Paradoxically, although estrogens stimulate breast cancers, risk rises markedly after menopause, when estrogens decrease. After menopause, estradiol falls and estrone is produced largely in fat by aromatase. Obesity women have high estrone, and both obesity and high estrone, but not estradiol, increase ER+ breast cancer risk after menopause. Low intra-tumor levels of enzymes converting estrone into estradiol, and elevation of enzymes that produce estrone both confer worse ER+ breast cancer outcome. Obesity mediates chronic inflammation through NF-κB driven cytokine expression. We showed contact between invading breast cancer cells and obese adipose tissue induces pro-inflammatory cytokines in both cell types that stimulate cancer stem cells (CSC) and drive metastasis. Our data suggest that cytokine induction after breast fat:cancer cell contact is estrogen:ER dependent, since blocking estrogen synthesis with the aromatase inhibitor, letrozole, reduced cytokine induction upon co-culture. While estradiol is known to oppose NF-κB mediated inflammation, the role of estrone in inflammation is not known and may differ from that of estradiol. We will study how estrone and estradiol, and changes in the ratios thereof before and after- menopause, may influence NF-κB activity and the pro-inflammatory state in obese postmenopausal women. We hypothesize that increased estrone:estradiol ratio after menopause shifts ER from an NF-κB co- repressor to a co-activator to up-regulate cytokines in obese adipocytes and cancer cells that drive CSC expansion and metastasis. We also posit that enzymes that convert estradiol to estrone may contribute to the poor outcome of ER+ cancers in obesity. Aim 1 will test if estradiol:ER decreases, estrone:ER increases or different estradiol:estrone ratios alter ER effects on NF-κB mediated induction of pro-inflammatory cytokine gene drivers of CSCs in ER+ breast cancer cells. To test in Aim 2 if estrone cooperates with obesity to drive ER+ breast cancer initiation and growth, we will co-culture human ER+ breast cancer cells with mammary adipocytes from women with different body mass index (BMI) +/- aromatase inhibition and test consequences on cytokine levels and CSC. We will also implant syngeneic breast cancers into lean or obese wild-type or aromatase knock-out mice to elucidate if host estrone mediates tumor promoting effects of obesity. Aim 3 will test if overexpression of HSD17B14, that converts estradiol to estrone, increases ER+ breast cancer cytokine expression and CSC in vitro, and increases tumor initiation and metastasis in vivo. We will also compare levels of estradiol/estrone interconversion enzymes in breast adipocytes and cancers from lean, overweight and obese women. A better understanding of the roles of estradiol and estrone may lead to new strategies for breast cancer prevention and treatment, and to changes in hormone replacement therapies. Shifting toward a higher estradiol: estrone ratio in serum or in breast cancer cells may prove to have therapeutic potential.

项目概要 肥胖会增加绝经后雌激素受体阳性（ER+）乳房的风险和不良预后 矛盾的是，尽管雌激素会刺激乳腺癌，但绝经后风险显着上升。 当绝经后雌激素减少时，雌二醇下降，雌酮主要在脂肪中产生。 肥胖女性的雌酮水平较高，肥胖和高雌酮水平都会增加，但雌二醇不会增加。 绝经后 ER+ 乳腺癌风险较低，肿瘤内将雌酮转化为雌二醇的酶水平较低。 以及产生雌酮的酶的升高都会导致 ER+ 乳腺癌的结果更差。 肥胖通过 NF-κB 驱动的细胞因子表达介导慢性炎症。 入侵的乳腺癌细胞和肥胖脂肪组织之间的相互作用会在这两种细胞中诱导促炎细胞因子 我们的数据表明细胞因子诱导。 乳房脂肪后：癌细胞接触是雌激素：ER 依赖性的，因为用 ER 阻断雌激素合成 芳香酶抑制剂来曲唑可减少共培养时的细胞因子诱导，而已知雌二醇则相反。 NF-κB 介导的炎症，雌激素在炎症中的作用尚不清楚，可能与雌激素不同 我们将研究雌酮和雌二醇及其比例在前后的变化。 更年期，可能会影响肥胖绝经后女性的 NF-κB 活性和促炎状态。 我们追求绝经后增加的雌酮：雌二醇比率将 ER 从 NF-κB 共转移 共激活剂的阻遏物，上调驱动 CSC 的肥胖脂肪细胞和癌细胞中的细胞因子 我们还假设将雌二醇转化为雌酮的酶可能有助于 肥胖症中 ER+ 癌症的不良预后 目标 1 将测试雌二醇：ER 是否减少、雌酮：ER 增加或是否增加。 不同的雌二醇：雌酮比例会改变 ER 对 NF-κB 介导的促炎细胞因子诱导的影响 ER+ 乳腺癌细胞中 CSC 的基因驱动因素 在目标 2 中测试雌激素是否与肥胖共同驱动。 ER+乳腺癌的发生和生长，我们将人类ER+乳腺癌细胞与乳腺共培养 来自不同体重指数 (BMI) +/- 芳香酶抑制的女性的脂肪细胞和测试结果 我们还将把同基因乳腺癌植入瘦或肥胖的野生型或 目标 3：芳香化酶敲除小鼠阐明宿主雌酮是否介导肥胖的肿瘤促进作用。 测试将雌二醇转化为雌酮的 HSD17B14 过度表达是否会增加 ER+ 乳腺癌细胞因子 我们还将比较体内的水平。 乳腺脂肪细胞中雌二醇/雌酮相互转化酶与瘦、超重和癌症的关系 更好地了解雌二醇和雌酮的作用可能会带来新的策略。 乳腺癌的预防和治疗，以及激素替代疗法的转变。 血清或乳腺癌细胞中较高的雌二醇：雌酮比率可能被证明具有治疗潜力。