NEW YORK (Reuters Health) - Estrogen may inhibit the growth of breast cancer cells that develop resistance to selective estrogen receptor modulators (SERMs) such as tamoxifen and raloxifene, according to two reports in the Journal of the National Cancer Institute for November 5.
Based on these findings, Dr. V. Craig Jordan and colleagues suggest that brief treatment of patients with acquired SERM resistance with physiologic levels of estrogen may inhibit tumor growth and re-establish SERM sensitivity.
Using a raloxifene-resistant cell model (MCF-7/Ral) they had developed, Dr. Jordan, at Northwestern University in Chicago, and associates explored the mechanism for raloxifene resistance and estrogen responsiveness. The cells were derived from estrogen receptor-alpha (ER-alpha)-positive human breast cancer (MCF-7) cells cultured for more than a year with raloxifene.
These pre-sensitized cells underwent apoptosis when subsequently exposed to low concentrations of estrogen.
The findings were similar when Dr. Jordan’s group examined tumors in vivo. Treatment with estradiol but not with raloxifene stimulated growth of MCF-7 tumors in ovariectomized athymic mice. Conversely, MCF-7/Ral tumors needed SERM treatment to grow. When SERM treatment was stopped after 9 weeks and estradiol was substituted, tumors shrank.
The research team was concerned that MCF-7/Ral cells were also resistant to tamoxifen. They advise that tamoxifen should not be given to patients with raloxifene-exposed breast cancer, and that aromatase inhibitors or fulvestrant may be better options.
In a second report in the same issue of the Journal, Dr. Jordan and his collaborators induced tamoxifen resistance by growing MCF-7 tumors in vivo in the presence of tamoxifen for 5 years.
In these tumors, treatment with fulvestrant, a drug that reduces the level of cellular ERs, switched the estradiol-induced apoptotic signal to an estradiol-induced growth signal.
“Future studies to integrate these novel results into clinical practice require a focus on enhancing estrogen-induced apoptosis with chemotherapy or radiation therapy and blocking tumor cell survival pathways with antibodies or tyrosine kinase inhibitors to HER2/neu and/or epidermal growth factor receptor,” the team concludes.
Reflecting on these findings, Dr. Daniel F. Hayes writes in an accompanying editorial that “the order in which serial endocrine therapies are administered might be critical, because the combination of fulvestrant and estrogen...produced results in diametric opposition to those expected.”
As a result, adds the physician with the University of Michigan in Ann Arbor, the standard practice of initiating fulvestrant therapy after breast cancer develops to resistance to tamoxifen and aromatase inhibitors “might be contraindicated.”
Source: J Natl Cancer Inst 2003;95:1565-1567,1586-1608. [ Google search on this article ]
MeSH Headings:DNA-Binding Proteins: Nuclear Proteins: Receptors, Estrogen: Receptors, Steroid: Transcription Factors: NF-kappa B: Receptors, Cytoplasmic and Nuclear: Genes, erbB-2: Genes, erbB: Drug Resistance, NeoplasmCopyright © 2002 Reuters Limited. All rights reserved. Republication or redistribution of Reuters content, including by framing or similar means, is expressly prohibited without the prior written consent of Reuters. Reuters shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. Reuters and the Reuters sphere logo are registered trademarks and trademarks of the Reuters group of companies around the world.
