DNA damage and breast cancer

Abstract

Cancer is intimately related to the accumulation of DNA damage, and repair failures (including mutation prone repair and hyperactive repair systems). This article relates current clinical categories for breast cancer and their common DNA damage repair defects. Information is included on the potential for accumulation of DNA damage in the breast tissue of a woman during her lifetime and the role of DNA damage in breast cancer development. We then cover endogenous and exogenous sources of DNA damage, types of DNA damage repair and basic signal transduction pathways for three gene products involved in the DNA damage response system; namely BRCA1, BRIT1 and PARP-1. These genes are often considered tumor suppressors because of their roles in DNA damage response and some are under clinical investigation as likely sources for effective new drugs to treat breast cancers. Finally we discuss some of the problems of DNA damage repair systems in cancer and the conundrum of hyper-active repair systems which can introduce mutations and confer a survival advantage to certain types of cancer cells.

Keywords: BRCA1; BRIT1; Classification of breast cancer; DNA damage; PARP-1; Triple-negative breast cancer; Tumor-initiating cells.

Figure 1

Mammary biology and cycles of remodeling requiring carefully controlled cell cycle regulation in which dysfunctional DNA repair mechanisms may instigate carcinogenesis. At any point during development and mammary remodeling, defects in repair of DNA damage can occur and become the basis for later oncogenesis. In this illustration, the relative numbers of remodeled structures (ducts and lobules) are illustrated by the mammary epithelial tree with green dots representing end buds and lobules and red dots representing lymph nodes.