(PQA2): Escape from breast tumor dormancy: convergence of obesity and menopause

描述(申请人提供)：超过75%的新诊断乳腺癌(BC)病例发生在绝经后(PM)妇女。在PM妇女中，肥胖与BC风险增加和预后不良有关。绝经后，肥胖女性患BC的风险比非肥胖女性高约50%。肥胖相关的乳腺肿瘤生长的机制尚不清楚，减轻肥胖对乳腺肿瘤发展的不利影响的策略也不存在。不幸的是，很少有研究关注肥胖对PM BC的影响。我们将验证这一新的假设，即肥胖通过促进PM女性血管表型的获得，促进乳腺肿瘤休眠的逃脱和促进肿瘤的生长。了解潜伏期肿瘤成为临床可检测肿瘤的机制，了解肥胖如何影响这一发育阶段，以及确定哪些妇女有患活动性BC的高风险，具有重要的临床意义。这里提出的新研究在肥胖、乳腺肿瘤休眠和更年期的独特趋同的背景下解决了这些目标。我们的初步研究表明，当用脂肪细胞条件培养液处理时，休眠的人BC细胞系在生化和功能上都发展出活跃的血管生成表型。目标1中提出的研究将确定脂肪细胞调节这种活性的机制，以及从绝经前和绝经后肥胖受试者分离的脂肪细胞诱导血管表型获得的能力是否不同。在目标2中，我们将利用三种临床上相关的不同绝经状态的BREAT肿瘤小鼠模型来确定肥胖增加是否导致乳腺肿瘤休眠和乳腺肿瘤进展的逃脱，识别这些病例中乳腺肿瘤发生的机制，并发现乳腺肿瘤生长的这一最早阶段的尿液生物标志物。在目标3中，我们将利用我们在发现非侵入性癌症生物标记物方面的经验来补充这些动物研究与患者的研究。我们将确定在肥胖和非肥胖女性以及接受/不接受减肥手术的女性中，尿液生物标记物是否可以预测肿瘤休眠的逃脱和血管生成表型的获得。我们聚集了一支由科学家和临床医生组成的独特而有成就的多学科团队，在以下具体目标的背景下进行了研究：1.确定脂肪细胞是否诱导休眠BC细胞获得血管生成表型2.确定肥胖是否调节PM BC 3肿瘤休眠的逃脱。为了确定在BC动物模型和患者中，尿液BC生物标志物的存在和新生血管是否作为逃脱乳腺癌休眠的哨兵，这些研究可能导致新的治疗、诊断和预后策略的开发，并改善BC患者的生存，最终也可能适用于其他人类癌症。

DESCRIPTION (provided by applicant): Over 75% of newly diagnosed cases of breast cancer (BC) occur in postmenopausal (PM) women. Obesity is associated with an increased risk and a poor prognosis of BC in PM women. After menopause, the risk of BC is ~50% higher in obese women than in those who are not. The mechanisms underlying obesity-related breast tumor growth are not known and strategies to alleviate the adverse effects of obesity on breast tumor development are nonexistent. Unfortunately, very few studies have focused on the effects of obesity on PM BC. We will test the novel hypothesis that obesity promotes the escape from breast tumor dormancy and promotes tumor growth by facilitating the acquisition of the vascular phenotype in PM women. It is of significant clinical interest to understand the mechanisms by which dormant tumors become clinically detectable ones, to learn how obesity affects this developmental step and to identify those women at high risk for developing active BC. The novel studies proposed here address these goals within the context of the unique convergence of obesity, breast tumor dormancy and menopause. Our preliminary studies suggest that dormant human BC cell lines develop an active angiogenic phenotype, both biochemically and functionally, when treated with adipocyte-conditioned media. The studies proposed in Aim 1 will determine the mechanisms by which adipocytes mediate this activity and whether adipocytes isolated from pre- and post-menopausal obese human subjects differ in their ability to induce the acquisition of the vascular phenotype. In Aim 2, we will utilize three clinically relevant breat tumor mouse models of differing menopausal status to determine whether increased adiposity results in the escape from breast tumor dormancy and breast tumor progression, to identify the mechanisms underlying breast tumor development in these cases and to discover urinary biomarkers of this earliest stage in breast tumor growth. In Aim 3, we will leverage our experience in the discovery of non- invasive cancer biomarkers to complement these animal studies with those in patients. We will determine whether urinary biomarkers predict the escape from tumor dormancy and the acquisition of the angiogenic phenotype in obese and non-obese women and in women who do/do not undergo bariatric surgery. We have brought together a unique and accomplished multidisciplinary team of scientists and clinicians to conduct the studies described within the context of the following Specific Aims: 1. to determine whether adipocytes induce the acquisition of the angiogenic phenotype in dormant BC cells 2. To determine whether obesity regulates the escape from tumor dormancy in PM BC 3. To determine whether the presence of urinary biomarkers of BC and neovascularization serve as sentinels of the escape from breast tumor dormancy in animal models of BC and in patients Taken together, these studies could result in the development of novel therapeutic, diagnostic and prognostic strategies and improved BC patient survival and may ultimately be applicable to other human cancers as well.