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: 10225652
• 负责人: JOYCE MARIE SLINGERLAND
• 金额: $ 35.11万
• 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/10225652
• 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; Mediating; Menopause; Mus; Neoplasm Metastasis; Neurodegenerative Disorders; Nuclear; Obesity; Outcome; Overweight; Pathway interactions; Post-Menopausal Hormone Replacement Therapy; Postmenopause; Prevention; Production; Prognosis; Risk; Role; Serum; Site; Testing; Therapeutic; Thinness; Tissues; Tumor Tissue; Woman; aggressive breast cancer; 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; mammary; new therapeutic target; overexpression; p65; prevent; promoter; self-renewal; stem cell expansion; 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.

项目摘要 肥胖增加了绝经后雌激素受体阳性（ER+）乳房的风险和不良预后 癌症。矛盾的是，尽管雌激素刺激乳腺癌，但更年期后的风险显着上升，但 当雌激素减少时。更年期后，雌二醇跌落和雌酮主要由脂肪产生 芳香酶。肥胖女性具有高雌激素，肥胖和高雌激素，但不增加雌二醇 ER+绝经后的乳腺癌风险。低肿瘤内水平的酶转化为雌二醇， 以及产生雌激素的酶的升高，这两者都会降低ER+乳腺癌结果。 肥胖通过NF-κB驱动的细胞因子表达介导慢性炎症。我们显示了接触 在入侵乳腺癌细胞和肥胖脂肪组织之间诱导两个细胞的促炎细胞因子 刺激癌症干细胞（CSC）并驱动转移的类型。我们的数据表明细胞因子诱导 乳腺脂肪之后：癌细胞接触是雌激素：ER依赖性，因为与雌激素合成与 芳香酶抑制剂，letrozole，在共培养后降低了细胞因子诱导。众所周知雌二醇反对 NF-κB介导的炎症，雌酮炎症的作用尚不清楚，可能与 雌二醇。我们将研究雌酮和雌二醇的方式以及其前后的比率变化 更年期可能会影响肥胖的绝经后妇女的NF-κB活性和促炎状态。 我们假设雌酮增加：绝经后的雌二醇比从NF-κB共同转移 在肥胖的脂肪细胞和驱动CSC的癌细胞中，引起共激活剂的阻遏物上调细胞因子 扩展和转移。我们还确认，将雌二醇转换为雌酮的酶可能有助于 肥胖症中ER+癌症的结果不佳。 AIM 1将测试雌二醇：ER减少，雌酮：ER增加或 不同的雌二醇：雌酮比改变ER对NF-κB介导的促炎细胞因子的诱导的影响 ER+乳腺癌细胞中CSC的基因驱动因素。在AIM 2中测试如果Estrone与肥胖驾驶合作 ER+乳腺癌的启动和生长，我们将与乳腺癌培养人类ER+乳腺癌细胞共同培养 来自不同体重指数（BMI）+/-芳香酶抑制和测试后果的女性的脂肪细胞 在细胞因子水平和CSC上。我们还将植入同性乳腺癌进入瘦或肥胖的野生型或 芳香酶敲除小鼠以阐明宿主雌酮是否介导肥胖的肿瘤促进作用。目标3意志 测试如果将雌二醇转化为雌酮的HSD17B14的过表达增加ER+乳腺癌细胞因子 体外表达和CSC，并在体内增加肿瘤倡议和转移。我们还将比较级别 乳腺脂肪细胞中的雌二醇/雌酮互转换酶的瘦肉，超重和 肥胖的妇女。更好地了解雌二醇和雌酮的作用可能会导致新的策略 预防乳腺癌和治疗，并改变激素替代疗法。转向一个 较高的雌二醇：血清或乳腺癌细胞中的雌酮比可能具有治疗潜力。