Cyr61-induced breast cancer: Clinical relevance and therapeutic development

Cyr61 诱导的乳腺癌：临床相关性和治疗开发

• 批准号: 7146334
• 负责人: RUTH LUPU
• 金额: $ 28.49万
• 依托单位: NORTHSHORE UNIVERSITY HEALTHSYSTEM
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-18 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7146334
• 关键词: breast neoplasms; mammary gland; breast neoplasms; mammary gland

DESCRIPTION (provided by applicant): The angiogenic factor cysteine-rich angiogenic protein 61 (Cyr61), a member of the CCN protein family, is overexpressed in a biologically aggressive subset of breast carcinomas. Moreover, forced expression of Cyr61 in breast cells promotes tumor formation in nude mice. Our clinical evaluation of Cyr61 (n=189 paraffin embedded tumor specimens) revealed that 30% of invasive breast carcinomas overexpress Cyr61, with Cyr61 expression inversely correlating with estrogen-receptor expression and erbB-2 overexpression. These findings support the notion that Cyr61 is a novel prognostic marker for breast cancer progression. We have recently described that Cyr61 functions as a survival factor capable of decreasing breast cancer cell chemosensitivity to the microtubule-targeting agent Taxol, the drug of choice in the treatment of metastatic breast cancer. Additionally, we demonstrated that functional blockage of the Cyr61 integrin receptor alpha-v-beta3 with arginine-glycine-aspartate (RGD) peptidomimetics markedly decreases cell viability in MCF-7 cells engineered to overexpress Cyr61, whereas it had no effect on Cyr61-negative control cells. Furthermore, alpha-v-beta3 blockade caused Taxol sensitivity in MCF- 7/Cyr61 cells to return to that observed in Cyr61-negative control cells. We hypothesize that high levels of Cyr61 produced and secreted by breast cancer epithelial cells, bind to alpha-v-beta3 to stimulate growth in an autocrine manner. We hypothesize that Cyr61-dependent activation of alpha-v-beta3-driven cellular signaling actively regulates breast cancer cell survival, thus promoting a more aggressive and chemoresistant breast cancer phenotype. Consequently, we hypothesize that by interfering with the Cyr61-alpha-v-beta3 signaling we may concomitantly block metastatic progression and Taxol resistance in breast carcinomas. Our studies are designed not only to evaluate whether the interaction between Cyr61 and alpha-v-beta3 is necessary and/or sufficient to induce breast cancer tumorigenicity, metastasis and chemoresistance but also to determine whether Cyr61 plays a role in the etiology of breast cancer. Therefore, this systematic approach will clarify the prognostic and predictive value of Cyr61 in breast cancer disease. We have formulated the following aims: 1) To determine the impact of Cyr61 expression in breast cancer progression and to evaluate the significance and clinical contribution to the treatment decision, 2) To assess the contribution of Cyr61 in the initiation and/or promotion of breast cancer. We will determine how Cyr61 contributes to the preneoplastic transformation of non-committed breast epithelial cells (normal cells) and whether Cyr61 overexpression triggers the malignant development of pre-neoplastic lesions in the breast, 3) To evaluate whether the specific silencing of Cyr61 gene expression modulates breast cancer progression and sensitivity to chemotherapy-induced cell damage, 4) To determine the involvement of the Cyr61 receptor alpha-v-beta3 integrin in Cyr61-induced breast cancer progression and chemoresistance, and 5) To determine whether a functional interaction between Cyr61 and alpha-v-beta3 is necessary and/or sufficient to induce malignant transformation, metastatic progression and/or chemoresistance in breast epithelial cells. In summary, we propose a previously unrecognized mechanism of breast cancer etiology, aggressive progression and chemosensitivity, in which the different compartments of breast cancer do not develop resistance through heritable genetic mutations, rather, as a result of their exposure to pro-angiogenic survival/growth factors present in the tumor microenvironment (i.e., Cyr61), become metastatic as well as refractory to chemotherapy by activating autocrine/paracrine pro-survival loops (i.e., Cyr61/alpha-v-beta3). In addition, we will evaluate the relevance of a Cyr61- triggered "Cyr61/alpha-v-beta3 integrin loop" as a novel predictive marker for response to chemotherapy in breast cancer.

描述（由申请人提供）：CCN蛋白质家族的成员，富含半胱氨酸的血管生成蛋白61（CYR61）在生物学上具有攻击性的乳腺癌子集中过表达。此外，乳腺细胞中CYR61的强迫表达促进了裸鼠的肿瘤形成。我们对CYR61的临床评估（N = 189石蜡嵌入的肿瘤标本）表明，30％的浸润性乳腺癌过表达CYR61，CYR61表达表达与雌激素受体 - 受体 - 受体表达和ERBB-2过表达的表达成反比。这些发现支持CYR61是乳腺癌进展的新型预后标记的观念。我们最近描述的是，CYR61是一种生存因子，能够降低乳腺癌细胞对微管靶向剂紫杉醇的化学敏感性，这是治疗转移性乳腺癌的首选药物。此外，我们证明了用精氨酸 - 甘氨酸 - 天冬氨酸 - 天冬氨酸（RGD）肽仪的功能阻塞显着降低了工程为过表达CYR61的MCF-7细胞中的细胞活力显着降低，而对CYR611-（CYR611-（CYR61）的影响没有影响。此外，α-V-BetA3阻断导致MCF-7/CYR61细胞中的紫杉醇敏感性返回到CYR61阴性对照细胞中观察到的细胞。我们假设由乳腺癌上皮细胞产生和分泌的高水平的CYR61与alpha-V-Beta3结合，以自分泌方式刺激生长。我们假设CYR61依赖性α-V-BetA3驱动的细胞信号的激活会积极调节乳腺癌细胞的存活，从而促进了更具侵略性和化学耐药的乳腺癌表型。因此，我们假设通过干扰CYR61-Alpha-V-BetA3信号传导，我们可能同时阻止乳腺癌中的转移性进展和紫杉醇耐药性。我们的研究不仅旨在评估CYR61与Alpha-V-Beta3之间的相互作用是否必要和/或足以诱导乳腺癌肿瘤性，转移和化学抗性，还可以确定CYR61是否在乳腺癌的病因中起作用。因此，这种系统的方法将阐明CYR61在乳腺癌疾病中的预后和预测价值。我们提出了以下目的：1）确定CYR61表达在乳腺癌进展中的影响，并评估对治疗决策的重要性和临床贡献，2）评估CYR61在乳腺癌开始和/或促进乳腺癌中的贡献。我们将确定CYR61如何促进非共同乳房上皮细胞（正常细胞）（正常细胞）以及CYR61过表达是否会触发乳房中的神经性病变的恶性发展，3）以评估CYR61基因表达的特定损害的特定损害，以确定乳腺癌的特定损害，以确定乳腺癌的特定损害，以确定乳腺癌的损害，以确定化学症状的促进性，以确定化学症状，以确定化学症状，以确定化学症状，并确定化学症状的损害。 CYR61受体α-V-BetA3整合素在CYR61诱导的乳腺癌进展和化学固定中，以及5）确定CYR61和Alpha-V-Beta3之间的功能相互作用是否必要和/或足以诱导恶性转化，转移性进展和/或化学疗法。总而言之，我们提出了一种先前无法识别的乳腺癌病因，侵略性进展和化学敏感性的机制，其中乳腺癌的不同区室不会通过可遗传的遗传突变来发展抵抗力，因为它们暴露于促肿瘤生长/生长因子中，在肿瘤微生物中存在于肿瘤的生长因子（即cyrastrestion）（即cyrastivion），因为它是cyrastiv的，因为它是Cyrastiv的。自分泌/旁分泌促生物循环（即Cyr61/alpha-v-beta3）。此外，我们将评估CYR61-触发的“ CYR61/Alpha-V-Beta3整合素环”的相关性，作为对乳腺癌化学疗法反应的新型预测标记。