The role of Src kinase in estrogen receptor-positive breast cancer proliferation

描述（由申请人提供）：已知雌激素（E2）可诱导雌激素受体阳性（ER+）乳腺癌细胞增殖。此外，与大多数癌症不同，ER+乳腺癌通常表达野生型肿瘤抑制因子p53，并且经常表达过度活跃的Src激酶。ER+乳腺癌细胞中涉及E2刺激的细胞周期进程的途径仍然未知。以前在生长因子刺激的成纤维细胞中的研究表明，有丝分裂需要Src家族激酶（SFKs）在细胞周期进展之前抑制p53。这种SFK细胞周期阻滞可以通过癌基因Myc的外源性表达来挽救。我的初步数据表明，在E2刺激后，ER+乳腺癌细胞系MCF7中存在类似的通路。在MCF 7细胞中，E2刺激的有丝分裂需要SFK活性，但在缺乏p53的MCF 7细胞中不需要。此外，E2刺激依赖于SFK活性的myc mRNA的表达。这种myc mRNA表达的增加似乎是由于mRNA的稳定性。该提议试图鉴定Src抑制p53的分子机制，可能通过调节p53的抑制剂Hdm2和Hdmx。该提案还旨在测试Src如何通过p53以及IMP 1调节myc mRNA的稳定性，IMP 1是一种已知稳定myc mRNA的RNA结合蛋白。总的来说，这个建议的目的是测试我的假设，Src激酶调节ER+乳腺癌细胞周期的进展，通过抑制p53功能和稳定Myc表达。

DESCRIPTION (provided by applicant): Estrogen (E2) is known to induce proliferation in estrogen receptor-positive (ER+) breast cancer cells. Additionally, ER+ breast cancers, unlike the majority of cancers, typically express wild-type tumor suppressor p53 and often express hyperactive Src kinase. The pathways involving E2-stimulated cell cycle progression in ER+ breast cancer cells remains unknown. Previous studies in growth factor-stimulated fibroblasts has shown that mitogenesis requires the Src family kinases (SFKs) to inhibit p53 prior to progressing through the cell cycle. This SFK cell cycle block can be rescued by exogenous expression of the oncogene, Myc. My preliminary data suggests a similar pathway functioning in the ER+ breast cancer cell line MCF7 after E2 stimulation. E2-stimulated mitogenesis in MCF7 cells requires SFK activity but not in MCF7 cells lacking p53. Additionally, E2 stimulates expression of myc mRNA dependent on SFK activity. This increase in myc mRNA expression appears to be due to mRNA stability. This proposal attempts to identify the molecular mechanism of Src inhibition of p53, likely through regulation of Hdm2 and Hdmx, inhibitors of p53. The proposal also aims to test how Src regulates myc mRNA stability through p53 as well as IMP1, an RNA-binding protein which is known to stabilize myc mRNA. Overall, this proposal aims to test my hypothesis that Src kinase regulates cell cycle progression in ER+ breast cancer by inhibiting p53 function and stabilizing Myc expression.