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Tamoxifen resistance in breast cancer: elucidating mechanisms
L C Dorssers1, S Van der Flier, A Brinkman
1Department of Pathology, Josephine Nefkens Institute, University Hospital Rotterdam, The Netherlands. dorssers@bidh.azr.nl
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.
Insights
Tamoxifen resistance in breast cancer is common. New research identifies breast cancer antiestrogen resistance (BCAR) genes, like BCAR1, that promote tamoxifen resistance by enabling estrogen-independent growth.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Tamoxifen is a widely used systemic treatment for estrogen receptor (ER)-positive breast cancer.
- Both intrinsic and acquired resistance to tamoxifen limit treatment efficacy in a significant proportion of patients.
- The precise mechanisms underlying tamoxifen resistance remain incompletely understood.
Purpose of the Study:
- To review recent findings from a functional screen for breast cancer antiestrogen resistance (BCAR) genes.
- To investigate the role of BCAR genes in the development of tamoxifen resistance in human breast cancer cells.
- To explore the association between BCAR gene expression and intrinsic tamoxifen resistance.
Main Methods:
- Functional screening of BCAR genes in human breast cancer cells.
- In vitro assays to assess estrogen-dependency and tamoxifen-resistance.
- Analysis of BCAR1/pl30Cas protein levels in ER-positive primary breast tumors.
Main Results:
- Individual BCAR genes can induce estrogen-independent and tamoxifen-resistant phenotypes in breast cancer cells in vitro.
- High levels of BCAR1/pl30Cas protein correlate with intrinsic resistance to tamoxifen in ER-positive breast tumors.
- These findings suggest a significant role for ER-independent growth pathways in tamoxifen resistance.
Conclusions:
- BCAR genes play a critical role in the development of tamoxifen resistance.
- BCAR1/pl30Cas is a potential biomarker for predicting intrinsic tamoxifen resistance.
- Understanding these resistance mechanisms is crucial for improving breast cancer therapy.