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

用于 ER-乳腺癌化学饮食预防/早期干预的靶标 p70S6K

• 批准号: 9215654
• 负责人: Dihua Yu
• 金额: $ 36.6万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-13 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9215654
• 关键词: 70-kDa Ribosomal Protein S6 Kinases; Accounting; Aerobic Exercise; American Cancer Society; Animal Model; Antibodies; Atypia; Automobile Driving; Biological Process; Biology; Breast Cancer Patient; Breast Epithelial Cells; Caloric Restriction; Cancer Model; Cessation of life; Chemoprevention; Clinic; Clinical Trials; Development; Diagnosis; Diet; Disease; Dose; ERBB2 gene; Early Intervention; Epidermal Growth Factor Receptor; Estrogen Antagonists; Estrogen receptor negative; Estrogen receptor positive; Event; FRAP1 gene; Fine needle aspiration biopsy; Gene Expression Profile; Genes; Glycogen Synthase Kinase 3; Glycolysis; Goals; High Risk Woman; Human; Hypoxia; Incidence; Injectable; Injection of therapeutic agent; Intervention; Lesion; Malignant Neoplasms; Mammary Neoplasms; Mammary gland; Metabolic; Metabolism; Molecular; Mouse Mammary Tumor Virus; Mus; Neoplastic Cell Transformation; Noninfiltrating Intraductal Carcinoma; Normal tissue morphology; Nutrient; Phase; Phosphorylation; Play; Prevention; Prevention strategy; Prevention trial; Preventive Intervention; Protein Array Analysis; Proteins; Raloxifene; Research; Resistance; Role; Signal Pathway; Signal Transduction; Subfamily lentivirinae; Tamoxifen; Testing; Toxic effect; Transgenic Mice; Translating; Translations; Up-Regulation; Wild Type Mouse; Woman; base; breast lesion; cDNA Arrays; cancer initiation; cancer prevention; cell transformation; chemo-dietary; clinical application; hypoxia inducible factor 1; in vivo; inhibitor/antagonist; interdisciplinary approach; knock-down; loss of function; malignant breast neoplasm; metabolomics; mortality; mouse model; novel; outcome forecast; overexpression; prevent; public health relevance; response; small hairpin RNA; sobriety; targeted agent; three dimensional cell culture; triple-negative invasive breast carcinoma; vector control

 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.

 描述（由适用提供）：美国癌症协会最近揭示了一个令人震惊的事实，即每2.3分钟就会被诊断出患有乳腺癌，每13分钟就有一个妇女就在美国死亡。为了减少乳腺癌的燃烧，并最终减少乳腺癌的死亡，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）和雷昔芬的化学预防试验表明，雌激素受体阳性（ER+）乳腺癌发生率的42％降低了42％，但没有有效预防ER阴性（ER-）乳腺癌的有效药物。为了制定乳腺癌的有效预防策略，我们需要确定驱动ER摄取启动和进展的关键改变，并用低毒性剂来针对预防。为了克服这一挑战，我们对具有高级TAM-耐药性（TAMR）异型的女性的精细针头抽吸活检进行了无偏反向相蛋白阵列（RPPA）分析，并确定了p70S6K超激活作为与TAMRESPIA相比的TAMR ATYPIA的主要信号改变。一致地，基因集富集分析（GSEA）表明，与乳腺癌患者配对的正常组织相比，AKT/P70S6K激活的基因早在ADH中就高度富集。此外，与野生型小鼠的乳腺腺体（MMTV-NEU/NDL2-5）相比，我们还检测到了ER-胸癌转基因小鼠模型（MMTV-NEU/NDL2-5）的异型病变的P70S6K过表达和高磷酸化；与非转化的乳腺上皮细胞（MEC）相比，我们在MCF10DCI（MCF10DCI）中观察到了相同的现象。 p70S6K激活功能失调多种生物学功能，例如增加HIF-1A，HIF-1A是低氧反应和细胞代谢的主要调节剂。实际上，我们发现P70S6K激活和ER-MEC的HIF-1A和糖酵解增加了P70S6K抑制剂治疗减少。这些导致我们假设MEC和乳腺异型中的P70S6K激活可以通过代谢失调来推动Er-乳腺癌的起始和进展，并且p70S6K靶向剂与饮食/代谢调节结合可能会阻止ER-乳腺癌。为了检验这一假设，我们将1）确定MEC早期转化和亚型转变为Er-乳腺癌中P70S6K激活的功能作用； 2）剖析p70s6k驱动的MEC转化和ER-非洲发展的分子机制； 3）通过使用低剂量的低毒性抑制剂与饮食/代谢调节相结合，探索靶向P70S6K的潜力，用于在ER乳腺肿瘤动物模型中进行化学预防/早期干预。拟议的研究的成功完成将带来I）对ER-乳腺癌启动的新理解，ii）ER乳腺癌的有效预防/干预策略。我们的研究发现很容易被转化为临床试验，作为高风险女性的一种新型预防策略，并最终减少与乳腺癌相关的死亡。