Tamoxifen Resistance in Breast Cancer

Abstract

Tamoxifen has been used for the systemic treatment of patients with breast cancer for nearly three decades. Treatment success is primarily dependent on 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 attributed to the pharmacology of tamoxifen, alterations in the structure and function of the ER, the interactions with the tumour environment and genetic alterations in the tumour cells. So far no prominent mechanism leading to resistance has been identified. The recent results of a functional screen for breast cancer antiestrogen resis- tance (BCAR) genes responsible for development of tamoxifen resistance in human breast cancer cells are reviewed. Individual BCAR genes can transform estrogen-dependent breast cancer cells into estrogen-independent and tamoxifen-resistant cells in vitro. Furthermore, high levels of BCAR1/pl30Cas protein in ER-positive primary breast tumours are associated with intrinsic resistance to tamoxifen treatment. These results indicate a prominent role for alternative growth control pathways independent of ER signalling in intrinsic tamoxifen resistance of ER-positive breast carcinomas. Deciphering the differentiation characteristics of normal and malignant breast epithelial cells with respect to proliferation control and regulation of cell death (apoptosis) is essential for understanding therapy response and development of resistance of breast carcinoma.

Integrin signalling adaptors: not only figurants in the cancer story

“…BCAR1, which encodes p130CAS, is upregulated in breast tumours resistant to tamoxifen 121,122 . Consistently, the over-expression of p130CAS in breast cancer cells induces proliferative signals that are not sensitive to treatment with either tamoxifen or oestrogen receptor antagonist fulvestrant 121,123 . Although it has been reported that a possible mechanism through which p130CAS induces tamoxifen resistance is its binding to BCAR3/AND34, a putative GEF for RALA, RAP, and RRAS GTPases 124 , the exact mechanism by which p130CAS and BCAR3 induce anti-oestrogen resistance remains unclear.…”

Pretreatment haemoglobin levels significantly predict the tumour response to primary chemotherapy in human breast cancer

“…In addition, in the absence of oxygen, P450 reductase interacts with anthracyclines, leading to cleavage of the anthracycline glycosidic bond and producing a molecule with no antitumour activity (Pan et al, 1981). In the CMF-treated group, most patients also received TAM concomitantly, which could have counterbalanced the cytotoxic resistance induced by hypoxia at least in part since the drug induces apoptosis that is ER mediated (Dorssers et al, 2001) and may not be influenced by tumour oxygenation. It has been demonstrated that the oxygenation status of human tumours is independent of clinical tumour size stage and grade (Wouters et al, 2002).…”

New approaches to the understanding of tamoxifen action and resistance.

“…These observations highlight the fact that different mechanisms for TR are likely and may involve adaptive changes as well as 'antiestrogen resistance genes'. Perhaps breast tumors in carriers of so called 'antiestrogen resistance genes' (Dorssers et al 2001) 274 www.endocrinology.org have a lesser ability to modulate MAPK and aromatase as adaptive processes than those with 'adaptive TR'.…”