Breast Cancer 1000 Project 2013-2014

Breast Cancer 1000 Project 2013-2014 Breast Cancer 1000 Project 2013-2014 The LaBaer group is pursuing studies to identify and characterize genes that play a role in resistance to clinical drugs used to treat breast cancer such as tamoxifen, fulvestrant and trastuzumab (Herceptin). In earlier work done for this project, we derived a series of cultured breast cancer cells that were either highly sensitive or naturally resistant to tamoxifen to study the factors that lead to drug resistance. These cell lines have been distributed to several labs and are used as a model to study the development of resistance. We are combining and analyzing multi-layered data from genomic, proteomic, and transcriptomic profiling of tamoxifensensitive and -resistant cell lines to generate a global picture of molecular mechanisms underlying tamoxifen resistance. Preliminary data showed that whereas sensitive cells share similar genomic profiles, the resistant counterparts are more variable, showing distinct profiles and suggesting a more diverse genetic background. Indeed, we have confirmed that regardless of their differential responses to tamoxifen in the matched cells, certain genes and proteins still responded to estrogen, which suggests that they may share some common regulator that is disrupted in the resistant cells. We are currently performing a computational analysis to identify the pathways involved in biological processes that could play a role in tamoxifen resistance. To extend our knowledge in breast carcinogenesis, we have begun to study how alterations in driver genes such as TP53 collaborate with other mutated genes to initiate cancer. Genomic studies indicate that breast cancer has a striking prevalence of somatic TP53 mutations (35%), which are particularly common in basal-like tumors. Patients with these aggressive basal-like tumors have fewer treatment options and respond poorly to current therapies. Successful treatment of basal cancer patients will likely require a combined approach that addresses both the p53 pathway as well as the modifier pathways that collaborate with p53 to cause cancer. We are performing functional studies to analyze the importance of co-driver mutations in order to find alternative targets that may offer better alternative for these patients. The LaBaer group has continued to develop, maintain and distribute a large gene collection, originally the BC1000 but now more than 10,000 human genes, for studies by the breast cancer community, which recently expanded in this last period with the addition of more than12,000 genes from our collaborators in the ORFeome Collaboration. This entire collection is available to all researchers in the scientific community athttp://dnasu.asu.edu/DNASU/