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

项目摘要 肥胖增加绝经后雌激素受体阳性（ER+）乳腺癌的风险和不良预后 癌奇怪的是，虽然雌激素会刺激乳腺癌，但绝经后的风险会显著上升， 当雌激素减少时。绝经后，雌二醇福尔斯下降，雌酮主要由脂肪产生， 芳香化酶肥胖妇女雌酮高，肥胖和高雌酮，但不是雌二醇，增加 绝经后ER+乳腺癌风险。肿瘤内将雌酮转化为雌二醇的酶水平低， 和产生雌酮的酶的升高都赋予更差的ER+乳腺癌结果。 肥胖通过NF-κ B驱动的细胞因子表达介导慢性炎症。我们有接触 乳腺癌细胞和肥胖脂肪组织之间的相互作用在两种细胞中诱导促炎细胞因子 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 乳腺脂肪后：癌细胞接触是雌激素：ER依赖，因为阻断雌激素合成与 芳香酶抑制剂来曲唑减少了共培养时的细胞因子诱导。虽然已知雌二醇 虽然雌酮是NF-κ B介导的炎症反应的重要因子，但雌酮在炎症反应中的作用尚不清楚，可能与雌酮不同。 雌二醇我们将研究雌酮和雌二醇，以及它们在治疗前后的比例变化- 绝经后肥胖妇女的NF-κ B活性和促炎状态可能受到影响。 我们假设绝经后雌酮：雌二醇比例增加，使ER从NF-κ B共表达转移到NF-κ B共表达。 阻遏物转化为共激活物，以上调肥胖脂肪细胞和癌细胞中驱动CSC的细胞因子 扩张和转移。我们还证实，将雌二醇转化为雌酮的酶可能有助于 肥胖者ER+癌症预后不良。目的1将测试雌二醇：ER是否降低，雌酮：ER是否增加， 不同雌二醇：雌酮比例改变ER对NF-κ B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。目的2：检测雌酮是否与肥胖协同作用， ER+乳腺癌的启动和生长，我们将人ER+乳腺癌细胞与乳腺癌细胞共培养。 来自具有不同体重指数（BMI）+/-芳香化酶抑制的女性的脂肪细胞和测试结果 对细胞因子水平和CSC的影响我们还将把同基因乳腺癌移植到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将 测试将雌二醇转化为雌酮的HSD17B14的过表达是否增加ER+乳腺癌细胞因子 在体外的肿瘤表达和CSC中，并且在体内增加肿瘤起始和转移。我们还将比较 雌二醇/雌酮互变酶在乳腺脂肪细胞和癌症从瘦，超重， 肥胖的女人更好地了解雌二醇和雌酮的作用可能会导致新的策略， 乳腺癌的预防和治疗，以及激素替代疗法的变化。转向A 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。

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.