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: 7687444
• 负责人: RUTH LUPU
• 金额: $ 30.05万
• 依托单位: MAYO CLINIC ROCHESTER
• 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/7687444
• 关键词: ABCB1 gene; Adjuvant Therapy; Age; Angiogenic Factor; Angiogenic Proteins; Animal Model; Anthracyclines; Antibodies; Apoptosis Inhibitor; Apoptotic; Arginine; Aspartate; Axillary lymph node group; Benign; Binding; Binding Sites; Biological; Biological Process; Blocking Antibodies; Breast; Breast Cancer Cell; Breast Carcinoma; Cancer Cell Growth; Cancer Etiology; Cancer Patient; Cancer cell line; Cell Adhesion; Cell Proliferation; Cell Survival; Cells; Chemotaxis; Classification; Clinical; Clinical Research; Clinical Trials; Commit; Cysteine; Data; Development; Diagnostic Neoplasm Staging; Disease; Dose; Doxorubicin; Drug resistance; Drug usage; Duct (organ) structure; Effectiveness; Endocrine; Epithelial; Epithelial Cells; Estrogen Antagonists; Estrogen Receptor Modulators; Estrogen Receptors; Estrogens; Etiology; Event; Exposure to; Future; Gene Expression; Gene Mutation; Glycine; Goals; Growth; Growth Factor; Heregulin; Hormones; Human; Humanized Monoclonal Antibody LM609; In Vitro; Integrin beta3; Integrins; Lesion; MCF7 cell; Maintenance; Malignant - descriptor; Malignant Neoplasms; Mammary Gland Parenchyma; Mediator of activation protein; Methodology; Microtubules; Molecular; Molecular Profiling; Multi-Drug Resistance; Mutate; Nature; Neoplasm Metastasis; Noninfiltrating Intraductal Carcinoma; Normal Cell; Nude Mice; Paclitaxel; Paraffin Embedding; Pattern; Pharmaceutical Preparations; Phenotype; Play; Predictive Value; Premalignant; Principal Investigator; Prognostic Factor; Prognostic Marker; Protein Family; RGD (sequence); RNA Interference; Refractory; Research Design; Research Personnel; Resistance; Resistance development; Role; Schedule; Signal Transduction; Site; Solid; Specimen; Stream; Structure; Surrogate Markers; Taxane Compound; Testing; Therapeutic; Tissue Microarray; Tissues; Treatment Protocols; Tumor stage; Tumorigenicity; Vascular Endothelial Cell; Vascular blood supply; Xenograft procedure; advanced disease; angiogenesis; autocrine; base; cancer therapy; cell injury; cell motility; cellular engineering; chemotherapeutic agent; chemotherapy; clinically relevant; clinically significant; cytotoxic; in vivo; independency; indexing; insight; lymph nodes; malignant breast neoplasm; malignant phenotype; member; neoplastic; novel; outcome forecast; overexpression; paracrine; peptidomimetics; preclinical study; prognostic; programs; protein expression; protein profiling; receptor; receptor expression; research clinical testing; response; response marker; synergism; taxane; therapeutic development; treatment duration; tumor; tumor progression; tumorigenesis

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)：血管生成因子半胱氨酸丰富的血管生成蛋白61(Cyr61)是CCN蛋白家族的成员，在乳腺癌的生物学侵袭性亚群中过度表达。此外，Cyr61在乳腺细胞中的强制表达促进了裸鼠体内肿瘤的形成。通过对189例乳腺癌石蜡包埋标本的临床分析，发现30%的浸润性乳腺癌组织中Cyr61过表达，且Cyr61的表达与雌激素受体的表达和erbB-2的过表达呈负相关。这些发现支持Cyr61是乳腺癌进展的一种新的预后标志物的观点。我们最近描述了Cyr61作为一个生存因子能够降低乳腺癌细胞对微管靶向药物紫杉醇的敏感性，紫杉醇是治疗转移性乳腺癌的首选药物。此外，我们还证明了用精氨酸-甘氨酸-天冬氨酸(RGD)肽模拟物功能阻断Cyr61整合素受体α-v-beta3显著降低了高表达Cyr61的MCF-7细胞的细胞存活率，而对Cyr61阴性对照细胞则没有影响。此外，阻断α-v-beta3可使MCF-7/Cyr61细胞对紫杉醇的敏感性恢复到Cyr61阴性对照细胞的水平。我们假设乳腺癌上皮细胞产生和分泌高水平的Cyr61，并与α-v-β3结合，以自分泌的方式刺激生长。我们假设，依赖于Cyr61的α-v-beta3驱动的细胞信号的激活积极地调节乳腺癌细胞的存活，从而促进更具侵袭性和化疗耐药的乳腺癌表型。因此，我们推测，通过干扰Cyr61-α-v-beta3信号，我们可能同时阻止乳腺癌的转移进展和紫杉醇耐药。我们的研究不仅旨在评估Cyr61和α-v-beta3之间的相互作用是否必要和/或足以诱导乳腺癌的发生、转移和化疗耐药，而且还旨在确定Cyr61是否在乳腺癌的病因学中发挥作用。因此，这一系统的方法将阐明Cyr61在乳腺癌疾病中的预后和预测价值。我们制定了以下目标：1)确定Cyr61的表达在乳腺癌进展中的影响，并评估其在治疗决策中的意义和临床贡献；2)评估Cyr61在乳腺癌发生和/或发展中的作用。我们将确定Cyr61如何参与未承诺的乳腺上皮细胞(正常细胞)的癌前转化，以及Cyr61过表达是否触发乳腺癌前病变的恶性发展；3)评估Cyr61基因表达的特异性沉默是否调节乳腺癌的进展和对化疗诱导的细胞损伤的敏感性；4)确定Cyr61受体α-v-β3整合素在Cyr61诱导的乳腺癌进展和化疗耐药中的作用；5)确定Cyr61和α-v-β3之间的功能相互作用是否必要和/或足以诱导乳腺上皮细胞的恶性转化、转移进展和/或化疗耐药。综上所述，我们提出了一种以前未知的乳腺癌病因学、侵袭性进展和化疗敏感性的机制，在这种机制中，乳腺癌的不同部分不会通过可遗传的基因突变产生耐药性，而是由于暴露于肿瘤微环境中的促血管生成生存/生长因子(即Cyr61)，通过激活自分泌/旁分泌促生存环(即Cyr61/α-v-beta3)而变得转移和对化疗耐药。此外，我们将评估Cyr61触发的“Cyr61/α-v-beta3整合素环”作为乳腺癌化疗反应的一种新的预测标志物的相关性。