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.
ER-positive breast cancers, which make up approximately 70% of breast cancers, have typically responded well to anti-estrogen treatment, however nearly half of this majority of breast cancer either are primarily resistant or develop resistance o this therapy. Characterization of the critical pathway that promotes cell growth in ER-positive breast cancer can provide critical knowledge for developing therapy. This proposal will provide insight into potential new therapeutic targets for ER-positive breast cancer as well as novel criteria to stratify patients for effective treatments.
|Iizuka, Shinji; Abdullah, Christopher; Buschman, Matthew D et al. (2016) The role of Tks adaptor proteins in invadopodia formation, growth and metastasis of melanoma. Oncotarget 7:78473-78486|