Evaluating the Genetic, Hormonal, and Exogenous Factors Affecting Somatic Copy Number Variation in Breast Cancer
Abstract
Breast cancer treatment has improved dramatically in the past decades. Fortunately, we can now offer many safe and effective therapies to newly diagnosed patients. However, there is one group that has not benefited from these advances: patients with a breast cancer subtype called basal-like cancer. From multiple perspectives, basal-like tumors appear to be quite different from other breast cancers. They behave more aggressively and tend to metastasize to important organs like the lungs and the brain. They do not express proteins that might make them sensitive to effective drugs, like anti-hormonal or anti-HER2 therapy. Perhaps most importantly, their genomes look very different from other breast cancer genomes. They contain large numbers of genetic changes called "copy number alterations": these are changes that affect how often a particular gene is present in a cell. Normally, every cell has two copies of each gene, one inherited from the mother and the other from the father. In basal-like breast cancers, some genes are present many more times than they should be, while other genes are present only once or have disappeared altogether. We do not know the origin of copy number alterations in basal-like breast cancer, but we suspect that they may be very important for tumor growth. It is possible that they arise after the tumor has already started developing and that their function is to help it thrive and adapt. However, it is also possible that copy number alterations already arise in normal breast cells. Surprisingly, we do not know whether the former or the latter is true, as we are currently lacking the methods to detect copy number alterations in normal tissues. The normal breast continuously produces specialized cells, so-called luminal epithelial cells, which are responsive to hormones and have the potential to make milk proteins. There is some evidence to suggest that copy number alterations may arise during the development of these luminal epithelial cells. In other words, we suspect that precursors of luminal epithelial cells may be particularly prone to accumulating copy number alterations, even in the healthy breast. It is very important to determine whether this is true because it could help explain the origins of basal-like breast cancer and why its genome contains so many copy number alterations. Most importantly, it could help us devise new ideas for preventing its development. In this project, we are proposing to develop methods for measuring how frequently copy number alterations arise in normal breast cells. We would like to know whether their number is increased in the cell type that is thought to give rise to basal-like breast cancer (the precursor of the luminal epithelial cells described above). Then, we will determine whether mutations in known breast cancer risk genes like BRCA1 exacerbate the generation of copy number alteration in different types of normal breast cells. This could help explain why women with BRCA1 mutations develop basal-like breast cancer more frequently than other cancer types. Finally, we would like to determine to what degree hormones affect how often copy number alterations arise in normal breast cells. It is very well documented that the more estrogen a woman is exposed to, the higher her risk of developing breast cancer. Why estrogen has this negative effect is not well understood, but we suspect that it may increase the number of copy number alterations in normal breast cells. If this were true, it would have significant implications for clinical decision-making. For example, pre-menopausal women should probably take care not to expose their breasts to additional harmful influences during certain stages of the menstrual cycle, when estrogen production is high and breast cells are already experiencing increased levels of copy number alterations. Medical imaging procedures like mammograms, X-ray, and CT examinations of the chest should probably
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510579
Entities
People
- Kamila Naxerova
Organizations
- United States Army