A Novel Clinically Relevant Tumor Suppressor in Human Breast Cancer

局部雌激素受体阳性(ER+)乳腺癌以晚期/转移性疾病形式复发 尽管是辅助性的，每年仍有数千名妇女接受抗雌激素治疗。已关联重复 具有内分泌治疗抵抗力，通常是致命的。有必要更好地预测哪些患者会 在没有辅助治疗的情况下，从辅助治疗中获益，或对辅助治疗反应差 尽量减少过度治疗，同时避免长期的、无效的治疗。我们发现了一种新的乳房 肿瘤抑制因子被称为G0/G1开关基因2(G0S2)。我们发现G0S2的表达频繁 在人类乳腺癌中被抑制，而且这种抑制与复发率的增加有关， 尤其是ER+患者接受辅助抗雌激素治疗。我们证明了G0S2可以 部分通过抑制MYC激活和G0S2缺失导致激活来拮抗致癌转化 MYC、PI3K和mTOR信号特征以及对PI3K和mTOR抑制剂的耐药性。MYC、PI3K和 MTOR激活是已知的抗雌激素抵抗机制，我们发现G0S2过表达 乳腺癌细胞中mTOR信号的抑制和对PI3K和mTOR的敏感性增加 抑制剂。MYC和PI3K/mTOR的激活最近被认为与介导抗雌激素抵抗有关 MYC驱动的乳腺肿瘤对MEK和PI3K/mTOR途径抑制剂具有耐药性。 我们的总体假设是G0S2抑制乳腺癌中的MYC和PI3K/mTOR信号，并且G0S2抑制乳腺癌中的PI3K/mTOR信号 G0S2的存在促进了针对ER+乳腺癌主导的现有治疗的更有效反应 到抑制复发。 我们的项目利用了体外和体内的分子、细胞和生化研究以及生物信息学。 接近了。这项小额拨款提案的目标是通过以下方式进一步巩固G0S2的抗癌效果 开发体外和体内模型，将在当前和未来的研究中使用，以确定 G0S2在抑制乳腺癌进展、复发、增强和预测中的作用 靶向生长因子途径和抗雌激素治疗的反应。由于人们对此知之甚少， 除了G0S2的分子功能外，该提议还旨在开发与直接机制有关的线索(S) G0S2行动。 为了为辅助治疗失败的乳腺癌发现新的、替代的靶向治疗，至关重要的是 进一步了解复发的机制。我们发现G0S2的表达经常被抑制 在人类乳腺癌中，这种抑制与复发和激活的通路有关 抗雌激素治疗耐药性可能在预测复发和机制方面有重要影响 针对目前处于临床开发中的这些通路的许多治疗方法的敏感性和耐药性。

Recurrence of local estrogen receptor positive (ER+) breast cancer in the form of advanced/metastatic disease despite adjuvant anti-estrogen therapy affects many thousands of women per year. Recurrence is associated with endocrine-therapy resistance and is usually fatal. There is a need to better predict which patients would do well without adjuvant treatment, benefit from adjuvant treatment, or respond poorly to adjuvant therapy to minimize overtreatment as well as to avoid prolonged, non-curative therapies. We discovered a novel breast cancer tumor suppressor called G0/G1 switch gene 2 (G0S2). We identified that G0S2 expression is frequently repressed in human breast cancer and that this repression is associated with increased rates of recurrence, especially for ER+ patients undergoing adjuvant anti-estrogen therapy. We demonstrate that G0S2 can antagonize oncogenic transformation in part by repressing MYC activation and that G0S2 loss causes activation of MYC, PI3K and mTOR signaling signatures and resistance to PI3K and mTOR inhibitors. MYC, PI3K and mTOR activation are known mechanisms of anti-estrogen resistance and we found that G0S2 overexpression in breast cancer cells leads to repression of mTOR signaling and increased sensitivity to PI3K and mTOR inhibitors. MYC and PI3K/mTOR activation have recently been implicated in mediating anti-estrogen resistance and MYC-driven breast tumors are resistant to MEK and PI3K/mTOR pathway inhibitors. Our overall hypothesis is that G0S2 suppresses MYC and PI3K/mTOR signaling in breast cancer and that the presence of G0S2 promotes more effective responses to existing therapies targeting ER+ breast cancer leading to inhibition of recurrence. Our project utilizes in vitro and in vivo molecular, cellular and biochemical based studies as well as bioinformatic approaches. The objective of this small grant proposal is to further solidify G0S2 anticancer effects by developing in vitro and in vivo models that will be used in current and future studies to definitively establish a role for G0S2 in the repression of breast cancer progression, recurrence, and in enhancing and predicting responses to targeted growth factor pathway and antiestrogen therapies. Since very little is known about the molecular functions of G0S2, the proposal is also designed to develop leads concerning the direct mechanism(s) of G0S2 actions. In order to uncover new, alternative targeted therapies for breast cancers that fail adjuvant therapy it is vital to further understand the mechanisms of recurrence. Our discovery that G0S2 expression is frequently repressed in human breast cancer and that this repression is associated with recurrence and activation of pathways linked to anti-estrogen therapy resistance may have major impact in predicting recurrence and mechanisms of sensitivity and resistance to many therapies targeting these pathways that are currently in clinical development.