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乳房的风险和不良预后 癌症。矛盾的是，尽管雌激素会刺激乳腺癌，但绝经后风险会显著上升， 当雌激素减少时。绝经后，雌二醇会下降，雌酮主要是在脂肪中由 芳香酶。肥胖女性有高雌酮，肥胖和高雌酮都会增加，但雌二醇不会增加 更年期后患乳腺癌的风险。肿瘤内将雌酮转化为雌二醇的酶水平较低， 产生雌酮的酶的升高都会导致更糟糕的ER乳腺癌预后。 肥胖通过NF-κB诱导的细胞因子表达介导慢性炎症。我们展示了联系方式 侵袭性乳腺癌细胞和肥胖脂肪组织之间的相互作用诱导两种细胞中的促炎细胞因子 刺激癌症干细胞(CSC)并推动转移的类型。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依赖的，因为阻止雌激素与雌激素的合成 芳香酶抑制剂来曲唑减少了共培养时细胞因子的诱导。而已知的雌二醇会反对 核因子-κB介导的炎症，雌酮在炎症中的作用尚不清楚，可能与 雌二醇。我们将研究雌酮和雌二醇是如何变化的，以及它们的比例在- 绝经，可能会影响肥胖绝经后妇女的NF-κB活性和促炎状态。 我们推测，绝经后雌酮/雌二醇比率增加会使ER从核因子-κB协同作用转变为雌激素受体。 抑制物为共激活物，可上调肥胖脂肪细胞和癌细胞中的细胞因子，从而驱动CSC 扩张和转移。我们还假设，将雌二醇转化为雌酮的酶可能有助于 肥胖患者内质网癌预后不良。目标1将测试雌二醇：ER减少，雌酮：ER增加或 不同雌、雌酮比例改变ER对NF-κB介导的促炎细胞因子的诱导作用 ER乳腺癌细胞中CSCs的基因驱动因素在Aim 2测试雌酮是否与肥胖症协同驱动 ER乳腺癌的发生和生长，我们将人ER乳腺癌细胞与乳腺共培养 不同体重指数(BMI)/芳香酶抑制的女性脂肪细胞及其检测结果 细胞因子水平与CSC的关系。我们还将把同基因乳腺癌植入瘦或肥胖的野生型或 芳香酶基因敲除小鼠，以阐明宿主雌酮是否介导肥胖的促癌作用。目标3将 检测雌激素转化为雌酮的HSD17B14过表达是否会增加ER乳腺癌细胞因子 在体外表达和CSC，并增加体内肿瘤的起始和转移。我们还将比较不同级别 瘦身、超重和乳腺癌患者乳腺脂肪细胞和癌组织中雌二醇/雌酮转换酶的变化 肥胖的女人。更好地理解雌二醇和雌酮的作用可能会导致新的治疗策略 乳腺癌的预防和治疗，以及激素替代疗法的变化。正在向 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.