Sean E. McGuire M.D., Ph.D.
Department of Molecular & Cellular Biology
Assistant Professor of Radiation Oncology
University of Texas MD Anderson Cancer Center
M.D.: Baylor College of Medicine
Ph.D.: Baylor College of Medicine
Residency: University of Texas MD Anderson Cancer Center
Cross-talk between DNA Damage Response and Growth Signaling in the Cell
A critical task for the proliferating cell is to coordinate its response to mitotic signals with mechanisms that ensure genomic integrity. The inability to integrate these processes can result in the inappropriate progression through the cell cycle in the presence of DNA damage, leading to the accumulation of mutations and chromosomal aberrations which can ultimately give rise to cancer. Indeed, a number of cancers have now been shown to arise from the inheritance of mutations that alter the ability to detect or repair DNA damage. For example, inherited breast cancer has been associated with germline mutations in BRCA1, BRCA2, CHEK2, ATM, NBS1, RAD50, BRIP1, PALB2, p53, and PTEN. An intriguing feature of these mutations is their tendency to give rise to cancers with a strong predilection for specific tissues in the body. For example, germ-line mutations in BRCA1 and BRCA2 confer an extremely high risk of cancers in steroid hormone responsive tissues such as the breast and ovary. The mechanisms underlying the tissue specificity of these tumors is currently unknown, but they strongly implicate an interaction between the molecular machinery of DNA damage repair and the specific growth signals to which these tissues normally respond.
The family of steroid receptor coactivators (SRC’s) are important molecules that coordinate steroid receptor signaling in a number of tissues including the breast and prostate. Currently, the laboratory is investigating the role of steroid receptor coactivators in mediating cellular responses to DNA damage-induced kinase signaling. Understanding these events will lend insight into both tumorigenesis and treatment of steroid responsive cancers.
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