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，并经常表达过度活跃的Src激酶。雌激素受体阳性乳腺癌细胞中e2刺激细胞周期进展的途径尚不清楚。先前对生长因子刺激成纤维细胞的研究表明，有丝分裂发生需要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，E2刺激后，ER+乳腺癌细胞系MCF7中也存在类似的途径。e2刺激的MCF7细胞有丝分裂需要SFK活性，而缺乏p53的MCF7细胞则不需要。此外，E2刺激myc mRNA的表达依赖于SFK活性。myc mRNA表达的增加似乎是由于mRNA的稳定性。本研究试图确定Src抑制p53的分子机制，可能是通过调控p53的抑制剂Hdm2和Hdmx。该提案还旨在测试Src如何通过p53和IMP1调节myc mRNA的稳定性，IMP1是一种已知的稳定myc mRNA的rna结合蛋白。总的来说，本提案旨在验证我的假设，即Src激酶通过抑制p53功能和稳定Myc表达来调节ER+乳腺癌的细胞周期进程。

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.