MEMORANDUM FOR: Science Writers and Editors on the Journal Press List

BCAR1/p130Cas Gene Is Involved in Tamoxifen Resistance Seen in Breast Cancer

January 13, 2000 (EMBARGOED FOR RELEASE 4 P.M. EST January 18)

Katherine Arnold, Deputy News Editor, Dan Eckstein, (301) 986-1891, ext. 112

A gene involved in the tamoxifen resistance seen in many breast cancer patients has been identified, and high levels of its expression in breast cancer patients have been associated with more rapid disease recurrence and increased resistance to tamoxifen therapy. About half of tumors that are estrogen receptor (ER) positive do not respond to tamoxifen, and almost all breast tumors that do respond to tamoxifen eventually develop tamoxifen-resistant metastases. The reasons for this tamoxifen resistance are not understood. Now, a research group led by Dr. Lambert C. J. Dorssers at the University Hospital Rotterdam, The Netherlands, has isolated and characterized one of the genes—BCAR1/p130Cas—involved in tamoxifen resistance. They have also measured Bcar1/p130Cas protein levels in breast cancer specimens to see if the levels are associated with disease progression and response to tamoxifen treatment. Articles by Brinkman et al. and van der Flier et al. at the University Hospital Rotterdam that summarize this work appear in the January 19 issue of the Journal of the National Cancer Institute.

Brinkman et al. worked with a model derived from the human breast cancer cell line ZR-75-1, a line known to be estrogen dependent. A unique collection of tamoxifen-resistant cell lines has been established that allows for the identification of genes involved in tamoxifen resistance. Now, the responsible gene in the particular BCAR1 locus (area) at human chromosome 16q has been identified. The complete coding sequence of the gene has been determined and has been identified as the human homologue of the rat p130Cas gene. Introduction of the BCAR1/p130Cas complementary DNA into tamoxifen-sensitive ZR-75-1 cells demonstrated that overexpression of this gene induces tamoxifen-resistant growth.

van der Flier et al. measured Bcar1/p130Cas protein levels in breast cancer tissues from more than 900 tumors. High Bcar1/p130Cas levels were associated with poor relapse-free survival and with poor overall survival. For example, at 96 months, the relapse-free survival probability of women with little or no detectable Bcar1/p130Cas protein was 50% compared with 32% for women with high levels. In addition, high levels of Bcar1/p130Cas were associated with poor response to tamoxifen in women with ER-positive tumors.

The authors conclude that high expression of Bcar1/p130Cas is a factor in tamoxifen resistance and disease progression. Therefore, they say that measurement of Bcar1/p130Cas may provide useful prognostic information for patients with breast cancer. The authors suggest further study of the BCAR1/p130Cas mechanism leading to tamoxifen-resistant breast cancer growth may contribute to development of new treatment strategies.

In an editorial, V. Craig Jordan, Ph.D., D.Sc., of the Northwestern University Medical School, Chicago, IL, notes that much work must be done to evaluate the role of BCAR1 in normal and malignant cells. He says that the goal of further study should be to refine the treatment of breast cancer by identifying those patients who would not be helped by tamoxifen.

Contact: M. deRomph, Rotterdam, The Netherlands, 31-10-463-4015; fax 31-10-463-3269. Editorial: Dr. V. Craig Jordan, Northwestern University, (312) 908-4148; fax (312) 908-1372.

Note: This memo to reporters is from the Journal staff and is not an official release of the National Cancer Institute (NCI) or Oxford University Press (OUP) nor does it reflect NCI or OUP policy. In addition, unless otherwise stated, all articles and items published in the Journal reflect the individual views of the authors and not necessarily the official points of view held by NCI, any other component of the U.S. government, OUP, or the organizations with which the authors are affiliated. Neither NCI nor any other component of the U.S. government nor OUP assumes any responsibility for the completeness of the articles or other items or the accuracy of the conclusions reached therein.



             
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