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

描述（由申请人提供）：超过75%的新诊断乳腺癌（BC）病例发生在绝经后（PM）妇女。肥胖与PM女性患BC的风险增加和预后不良有关。绝经后，肥胖妇女患BC的风险比非肥胖妇女高50%。肥胖相关乳腺肿瘤生长的机制尚不清楚，减轻肥胖对乳腺肿瘤发展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。我们将验证肥胖通过促进PM女性血管表型的获得来促进乳房肿瘤休眠和肿瘤生长的新假设。了解潜伏肿瘤转变为临床可检测肿瘤的机制，了解肥胖如何影响这一发展步骤，并确定那些具有发展为活动性BC高风险的女性，具有重要的临床意义。本文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，休眠的人BC细胞系在生物化学和功能上都表现出活跃的血管生成表型，当用脂肪细胞条件培养基处理时。Aim 1中提出的研究将确定脂肪细胞介导这种活性的机制，以及从绝经前和绝经后肥胖人类受试者中分离的脂肪细胞诱导血管表型获得的能力是否不同。在Aim 2中，我们将利用三种不同绝经状态的临床相关乳腺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逸，确定这些病例中乳腺肿瘤发展的机制，并发现乳腺肿瘤生长早期的尿液生物标志物。在目标3中，我们将利用我们在发现非侵入性癌症生物标志物方面的经验来补充这些动物研究与患者研究。我们将确定尿液生物标志物是否能预测肥胖和非肥胖女性以及接受/不接受减肥手术的女性摆脱肿瘤休眠和获得血管生成表型。我们汇集了一个由科学家和临床医生组成的独特的、有成就的多学科团队，在以下具体目标的背景下进行研究：以确定脂肪细胞是否诱导休眠BC细胞获得血管生成表型2。目的：确定肥胖是否调节pmbc3中肿瘤休眠的逃逸。为了确定BC和新生血管的尿液生物标志物的存在是否可以作为乳腺癌动物模型和患者摆脱乳腺癌休眠的哨兵。总之，这些研究可能会导致新的治疗、诊断和预后策略的发展，提高BC患者的生存率，并可能最终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.