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（由申请人提供）：美国癌症协会最近披露了一个发人深省的事实，仅在美国，每 2.3 分钟就有一名女性被诊断出患有乳腺癌，每 13 分钟就有一名女性死于乳腺癌。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出令人鼓舞的结果，但我们迫切需要制定更有效的预防和早期干预策略。雌激素受体阳性 (ER+) 乳腺癌发病率降低 42%，但没有有效的药物可以预防 ER 阴性 (ER-) 乳腺癌。 为了制定有效的 ER- 乳腺癌预防策略，我们需要确定驱动 ER 的关键改变。 - 病变的发生和进展，并用低毒性药物进行预防 为了克服这一挑战，我们对具有高级别 Tam 耐药性的女性的细针抽吸活检进行了公正的反相蛋白阵列 (RPPA) 分析。 (TamR) 异型性，并确定与 TamR 异型性相比，p70S6K 过度激活是 TamR 异型性的主要信号改变。基因集富集分析 (GSEA) 一致表明，与 ADH 相比，Akt/p70S6K 激活基因早在 ADH 中就高度富集。此外，我们还在转基因小鼠模型的异型病变中检测到 p70S6K 过度表达和过度磷酸化。 ER-乳腺癌（MMTV-neu/NDL2-5）与野生型小鼠乳腺（MGD）相比；我们在早期三阴性乳腺癌（TNBC）模型MCF10DCIS中观察到与非乳腺癌模型相比相同的现象。 - 转化的乳腺上皮细胞 (MEC) 激活会失调多种生物功能，例如增加缺氧反应和细胞的主要调节因子 HIF-1a。事实上，我们发现 p70S6K 激活的和 ER-MEC 增加了 HIF-1a 和糖酵解，而 p70S6K 抑制剂治疗会减少这些现象，这使我们发现 MEC 和乳腺异型性中的 p70S6K 激活可以驱动 ER 的发生和进展。 - 代谢失调导致乳腺癌，p70S6K 靶向药物与饮食/代谢调节相结合可以预防 ER-乳腺癌。为了检验这一假设，我们将 1) 确定 p70S6K 激活在 MEC 早期转化和异型性转变为 ER-乳腺癌中的功能作用；2) 剖析 p70S6K 驱动的 MEC 转化和 ER-异型性进展的分子机制；探索通过使用低剂量的低毒性抑制剂结合饮食/代谢调节来靶向 p70S6K 进行化学饮食预防/早期干预的潜力所提出的研究的成功完成将带来 i) 对 ER-乳腺癌发生的新认识，以及 ii) ER-乳腺癌的有效预防/干预策略。临床试验作为高危女性的新型预防策略，并最终减少乳腺癌相关的死亡。