Target p70S6K for Chemodietary Prevention/Early Intervention of ER- Breast Cancer

 美国癌症协会最近披露了一个令人清醒的事实，即每2.3分钟就有一名妇女被诊断患有乳腺癌，每13分钟就有一名妇女死于乳腺癌。为了减轻乳腺癌的负担，并最终减少乳腺癌死亡，我们迫切需要制定更有效的预防和早期干预策略。尽管抗雌激素他莫昔芬（Tam）和雷洛昔芬的化学预防试验显示雌激素受体阳性（ER+）乳腺癌发病率降低了42%，但没有有效的药物预防ER阴性（ER-）乳腺癌。为了开发有效的ER-乳腺癌预防策略，我们需要确定驱动ER-病变起始和进展的关键改变，并用低毒性药物靶向它们进行预防。为了克服这一挑战，我们对高级别TamR耐药（TamR）乳腺癌妇女的细针穿刺活检进行了无偏倚的反相蛋白阵列（RPPA）分析，并将p70 S6 K超活化确定为TamR乳腺癌与TamR敏感乳腺癌相比的主要信号改变。一致的是，基因集富集分析（GSEA）显示，Akt/p70 S6 K激活的基因高度富集，早在ADH相比，配对的正常组织从乳腺癌患者。此外，与野生型小鼠的乳腺（MGD）相比，我们还检测到ER-乳腺癌的转基因小鼠模型（MMTV-neu/NDL 2 -5）的乳腺病变中的p70 S6 K过表达和过度磷酸化;与非转化的乳腺上皮细胞（MEC）相比，我们在早期三阴性乳腺癌（TNBC）模型MCF 10 DCIS中观察到相同的现象。p70 S6 K激活失调多种生物学功能，例如，增加HIF-1a，缺氧反应和细胞代谢的主要调节剂。事实上，我们发现p70 S6 K激活的和ER-MEC具有增加的HIF-1 α和糖酵解，其被p70 S6 K抑制剂处理所减弱。这些使我们假设MEC和乳腺癌中的p70 S6 K活化可以通过代谢失调驱动ER-乳腺癌的起始和进展，并且p70 S6 K靶向剂与饮食/代谢调节组合可以预防ER-乳腺癌。为了验证这一假设，我们将1）确定p70 S6 K激活在MEC早期转化和ER-乳腺癌转化中的功能作用：2）剖析p70 S6 K驱动的MEC转化和ER-乳腺癌进展的分子机制;和3）通过使用低剂量的低毒性抑制剂，结合饮食/代谢调节，用于ER-乳腺肿瘤动物模型中的化学饮食预防/早期干预。拟议研究的成功完成将带来i）对ER-乳腺癌启动的新理解，以及ii）ER-乳腺癌的有效预防/干预策略。我们的研究结果可以很容易地转化为临床试验，作为高危女性的一种新的预防策略，并最终减少乳腺癌相关的死亡。

 DESCRIPTION (provided by applicant): The American Cancer Society recently revealed the sobering fact that every 2.3 minutes one woman is diagnosed with breast cancer and every 13 minutes one woman dies of breast cancer in the U.S. alone. To reduce the burden of breast cancer, and ultimately, reduce breast cancer death, we urgently need to develop more effective prevention and early intervention strategies. Although chemoprevention trials of anti-estrogenic tamoxifen (Tam) and raloxifene have shown an encouraging 42% decrease in estrogen receptor positive (ER+) breast cancer incidence, there is no effective agent for prevention of ER negative (ER-) breast cancer. To develop effective prevention strategies for ER- breast cancer, we need to identify key alterations driving ER- lesion initiation and progression and target them with low-toxicity agents for prevention. To surmount this challenge, we have performed an unbiased reverse phase protein array (RPPA) analysis on fine needle aspiration biopsies of women with high grade Tam-resistant (TamR) atypia and identified p70S6K hyper activation as a major signaling alteration in TamR atypia compared to Tam-sensitive atypia. Consistently, gene set enrichment analysis (GSEA) revealed that Akt/p70S6K-activated genes are highly enriched as early as in ADH compared to paired normal tissue from breast cancer patients. In addition, we also detected p70S6K overexpression and hyper phosphorylation in atypia lesions of a transgenic mouse model of ER- breast cancer (MMTV-neu/NDL2-5) compared to the mammary glands (MGD) of wild type mice; we observed the same phenomenon in MCF10DCIS, an early stage triple negative breast cancer (TNBC) model, compared to non- transformed mammary epithelial cells (MECs). p70S6K activation dysregulates multiple biological functions, e.g., increasing HIF-1a, a master regulator of hypoxic responses and cellular metabolism. Indeed, we found that p70S6K-activated and ER- MECs had increased HIF-1a and glycolysis which are diminished by p70S6K inhibitor treatment. These led us to hypothesize that p70S6K activation in MECs and in mammary atypia can drive initiation and progression of ER- breast cancer by metabolic dysregulation, and that p70S6K-targeting agents combined with dietary/metabolic modulation may prevent ER- breast cancer. To test this hypothesis, we will 1) determine the functional roles of p70S6K activation in MEC early transformation and atypia transition to ER- breast cancer; 2) dissect the molecular mechanisms of p70S6K-driven MEC transformation and ER- atypia progression; and 3) explore the potential of targeting p70S6K by using low doses of low-toxicity inhibitors, in combination with dietary/metabolic modulation, for chemo-dietary prevention/early intervention in ER- mammary tumor animal models. The successful completion of the proposed studies will bring i) new understanding of ER- breast cancer initiation, and ii) effective prevention/intervention strategies for ER- breast cancer. Our research findings could be readily translated into clinical trials as a novel prevention strategy for high risk women and, ultimately, reduce breast cancer-related death.