Mechanisms behind hyperglycemia-associated breast cancer risk and progression

 描述（由申请人提供）：流行病学证据表明，患有糖尿病的女性患乳腺癌的风险增加，糖尿病可能会显著增加癌症患者的死亡率。重要的是，非洲裔美国人和西班牙裔/拉丁裔妇女不成比例地受到糖尿病及其并发症的影响。同时，这些妇女患乳腺癌的结果最差。糖尿病和癌症有许多共同的风险因素，但这两种疾病之间的潜在生物学联系尚不完全清楚。我们的初步研究为高葡萄糖（HG）如何在乳腺上皮细胞中发挥作用提供了新的见解。将培养的转化（MCF-7）和正常（MCF-10A）乳腺上皮细胞暴露于临床相关水平的葡萄糖显著抑制肿瘤抑制因子p53乙酰化，并且因此加成性地促进肿瘤细胞增殖并消除DNA损伤诱导的凋亡。重要的是，核磷酸酶PP 2Cd的激活在此过程中发挥作用。此外，我们首次证明BRAC 1与p300和p53形成复合物，并且通过DNA损伤增加BRAC 1的磷酸化增强了p53向p300的募集，并促进了随后的p53乙酰化。在被HG激活后，PP 2Cd使BRAC 1去磷酸化并抑制其对p53乙酰化的上调作用。这些结果不仅可以解释高血糖导致的上皮细胞增殖和肿瘤发生增加，而且还可以解释糖尿病导致的乳腺癌风险增加。基于这些结果，我们假设高血糖症通过参与PP 2 Cd激活的途径抑制肿瘤抑制因子BRCA 1和p53的功能，并抑制DNA损伤诱导的细胞凋亡和细胞周期停滞，诱导上皮细胞增殖以及乳腺癌的发生和发展。本研究从以下三个方面对这一假说进行了验证：（1）探讨汞诱导PP 2Cd活化的机制：（2）探讨PP 2Cd使乳腺上皮细胞BRAC 1去磷酸化并拮抗p53乙酰化的分子机制;（3）通过链脲佐菌素（STZ）诱导的或高脂饮食，在体内表征高血糖对乳腺癌的发展和化疗的影响。STZ诱导的糖尿病裸鼠携带MCF-7细胞和来自糖尿病或非糖尿病患者的乳腺癌标本。这些研究为研究这种连接糖尿病和乳腺癌的新机制奠定了基础，目的是定义一种新的途径并提供额外的治疗靶点。乳腺癌尤其影响到很大一部分非裔美国人和西班牙裔妇女，并构成社会的重大财政负担。因此，研究高血糖对致癌信号网络的影响是一个具有相当大的翻译意义的新问题，将是揭示这种健康差异的重要一步。

 DESCRIPTION (provided by applicant): Epidemiologic evidence suggests that women with diabetes have increased risk of breast cancer and that diabetes may dramatically increase mortality in patients with cancer. Importantly, African-American and Hispanic/Latina women are disproportionately affected by diabetes and its complications. Concurrently, these women have worst outcome from breast cancer. Diabetes and cancer share many risk factors, but potential biologic links between the two diseases are incompletely understood. Our preliminary studies have provided new insights into how high glucose (HG) functions in breast epithelial cells. Exposure of cultured transformed (MCF-7) and normal (MCF-10A) breast epithelial cells to clinically relevant levels of glucose dramatically suppresses the tumor suppressor p53 acetylation, and, consequently, additively promotes tumor cell proliferation and abrogates DNA damage-induced apoptosis. Importantly, activation of nuclear phosphatase PP2Cd plays a role in this process. In addition, we for the first time demonstrate that BRAC1 forms a complex with p300 and p53, and an increased phosphorylation of BRAC1 by DNA damage enhances the recruitment of p53 to p300 and facilitates subsequent p53 acetylation. Upon activation by HG, PP2Cd dephosphorylates BRAC1 and inhibits its up-regulatory effect on p53 acetylation. These results may not only provide explanation for increased epithelial proliferation and tumorigenesis by hyperglycemia, but also increased breast cancer risk by diabetes. Based on these results we hypothesize that hyperglycemia, via a pathway that involved in PP2Cd activation, suppresses the tumor suppressor BRCA1 and p53 function and inhibits DNA damage-induced apoptosis and cell cycle arrest, inducing proliferation in the epithelium and the initiation and development of breast cancer. This hypothesis will be tested in three specific aims: (1) To explore the mechanisms underlying HG-induced PP2Cd activation; (2) To investigate the molecular mechanism by which PP2Cd dephosphorylates BRAC1 and antagonizes p53 acetylation in breast epithelial cells; (3) To characterize the effects of hyperglycemia on the development and chemotherapy of breast cancer in vivo using streptozotocin (STZ)-induced or high fat diet/STZ-induced diabetic nude mice bearing MCF-7 cells and breast cancer specimens from patients with or without diabetes. These studies set the stage for investigating this novel mechanism connecting diabetes and breast cancer with a goal of defining a new pathway and providing additional targets for therapy. Breast cancer in particular affects a large sector of African-American and Hispanic women and constitutes a significant financial burden for the society. Thus, studying the influence of hyperglycemia on oncogenic signaling networks is a novel question with considerable translational implications and would be a significant step in shedding light on this health disparity.