A Genetic Basis for Luminal and Basal-Type Breast Cancer

In the Western world, breast cancer not only is the most frequently diagnosed cancer in women, but also the second leading cause of cancer death. Clinically, breast cancer is a heterogeneous disease. About two-thirds of breast cancer patients survive their disease, whereas, one-third of breast cancer patients will die of metastases of their primary cancer within 15 years from diagnosis. Therefore, it is important for clinicians to accurately predict the prognosis and most appropriate therapy for each breast cancer patient. However, appropriate molecular targets have as yet not been identified for most breast cancer subtypes, implying suboptimal treatment for a significant fraction of the breast cancer patients. Thus, a better understanding of the disease is needed to improve upon current methods to treat breast cancer patients. In this thesis, we set out to determine the genetic basis for the two major subtypes of breast cancer, by mutation screening of 27 known cancer genes in a model of human breast cancer cell lines. Two distinct mutation profiles were identified: a “luminal mutation profile” among luminal-type breast cancer cell lines and a “basal mutation profile” among basal-type breast cancer cell lines. The gene mutation profiles give insight in the mechanisms of breast carcinogenesis. For example, we found that mutation and hypermethylation of the E-cadherin gene, two mechanisms involved in tumor suppressor gene inacativation, associated with each of the two breast cancer subtypes. This challenges the paradigm that genetic and epigenetic inactivation of a tumor suppressor gene are two means to the same end. Importantly, the results of this thesis provide a further refinement of current molecular breast cancer classification and may aid the development of new treatment modalities th! at target the here identified molecular markers.