The role of BCAR4 in tamoxifen resistant breast cancer

textabstractBreast cancer is one of the most common cancers in women, and it is the second leading cause of cancer-related deaths, just behind lung cancer. The antiestrogen tamoxifen has been successfully used for over three decades to treat patients with estrogen receptor alpha-positive breast cancer patients. However, resistance to this antiestrogen presents a major problem in the treatment of these patients. The breast cancer antiestrogen resistance 4 (BCAR4) gene was identified earlier as a gene capable of inducing tamoxifen resistance in breast cancer cells. The objectives of the research described in this thesis were to functionally characterize BCAR4, to establish its clinical relevance, and to unravel the mechanisms of tamoxifen resistance induced by BCAR4. The species and tissue specific expression of BCAR4 strongly suggest a role for the gene in mammalian early development and pregnancy. In human breast cancer, high BCAR4 mRNA levels in primary tumors predict tamoxifen resistance, and associate with cancer aggressiveness. BCAR4-induced tamoxifen resistance requires activation of ERBB2 and ERBB3 signaling, but the mechanisms by which BCAR4 activates these receptors are currently unknown. Tamoxifen resistance in breast cancer cells expressing BCAR4 can be reverted by treating them with an ERBB2 inhibitor. This implies that this combination of anticancer agents is more effective at inhibiting proliferation of these cells. BCAR4 expression in primary breast cancer identifies a subgroup of patients that could benefit from ERBB2-targeted therapies combined with tamoxifen treatment. This argues for clinical studies evaluating the value of BCAR4 as a biomarker and the possible benefits of the combined treatments for this patient subgroup