Tamoxifen resistance in breast cancer - Elucidating mechanisms

Tamoxifen has been used for the systemic treatment of patients with breast cancer for nearly three decades. Treatment success is primarily dependent o n the presence of the estrogen receptor (ER) in the breast carcinoma. While about half of patients with advanced ER-positive disease immediately fail to respond to tamoxifen, in the responding patients the disease ultimately progresses to a resistant phenotype. The possible causes for intrinsic and acquired resistance have been attribu ted to the pharmacology of tamoxifen, alterations in the structure and func tion of the ER, the interactions with the tumour environment and genetic al terations in the tumour cells. So far no prominent mechanism leading to res istance has been identified. The recent results of a functional screen for breast cancer antiestrogen re sistance (BOAR) genes responsible for development of tamoxifen resistance i n human breast cancer cells are reviewed. Individual BCAR genes can transfo rm estrogen-dependent breast cancer cells into estrogen-independent and tam oxifen-resistant cells in vitro. Furthermore, high levels of BCAR1/p130Cas protein in ER-positive primary breast tumours are associated with intrinsic resistance to. tamoxifen treatment. These results indicate a prominent rol e for alternative growth control pathways independent of ER signalling in i ntrinsic tamoxifen resistance of ER-positive breast carcinomas. Deciphering the differentiation characteristics of normal and malignant bre ast epithelial cells with respect to proliferation control and regulation o f cell death (apoptosis) is essential for understanding therapy response an d development of resistance of breast carcinoma.