© 2002 by Oxford University Press
Journal of the National Cancer Institute, Vol. 94, No. 15, 1174-1175,
August 7, 2002
© 2002 Oxford University Press
CORRESPONDENCE |
RESPONSE: Re: Effect of Long-Term Estrogen Deprivation on Apoptotic Responses of Breast Cancer Cells to 17
-Estradiol and The Two Faces of Janus: Sex Steroids as Mediators of Both Cell Proliferation and Cell Death
Affiliations of authors: A. M. Soto, C. Sonnenschein, Department of Anatomy and Cellular Biology, Tufts University, Boston, MA.
Correspondence to: Ana M. Soto, M.D., Department of Anatomy and Cellular Biology, Tufts University School of Medicine, Boston, MA 02111 (e-mail: ana.soto{at}tufts.edu).
The comments by Jordan et al. focus on yet another variation of the phenomenon of estrogen-induced tumor regression. The use of antiestrogens in the treatment of breast cancer was predicated on the idea that, if estrogens induce cancer growth, then antiestrogens should do the opposite. However, the clinical studies that resulted in the adoption of tamoxifen as the drug of choice in the treatment of estrogen receptor-positive breast cancer compared the effectiveness of this treatment with that of the estrogen diethylstilbestrol (DES). Both treatments were equally effective, but tamoxifen was preferred over DES because it produced less severe side effects. In addition, tamoxifen was also intuitively more acceptable to researchers and physicians than DES because estrogens were expected to make a tumor grow faster; the notion that estrogens might also induce tumor regression was counterintuitive.
The results of Song (1), Jordan (2), and our own group (3) are consistent with the notion that estrogens induce cell death in estrogen receptor-positive breast cancer cell lines that undergo selective pressure either by estrogen withdrawal or by exposure to tamoxifen. What is still unclear, however, is whether estrogens act directly on the epithelial tumor cells (as suggested by studies carried out in cell culture), indirectly through the stroma, or on both cell types.
Studies on estrogen-induced apoptosis (1,3) and tumor regression (2) also highlight the plasticity of the cellular and tissue response to estrogens. Under selective pressure, a cell line that would normally respond to estrogen by increasing its proliferation rate may evolve into one that expresses an apoptotic response. With further selective pressure, these cells would revert to a phenotype in which estrogens induce cell proliferation (4). In addition to being a worthy phenomenon to study, phenotypic plasticity warns us against the danger of selecting for unwanted phenotypes by administering hormone agonist or antagonist treatments for prolonged periods. For example, what has been the rationale behind administering tamoxifen for 5 or more years? We now know that patients treated continuously with tamoxifen for 5 years have a substantially higher disease-free survival rate than those treated for longer periods (5). Therefore, would the disease-free survival rate of women treated with tamoxifen for a shorter period be even better than that of those treated for 5 years? Can a shorter treatment period avert the selection for cells that become resistant to tamoxifen? Work by Jordan's group suggests that this may be the case (2).
Turning now to clinical assessment, the already available wealth of clinical data should be reviewed to determine the optimal duration of treatment with hormone antagonists to avoid resistance. Furthermore, studies on the long-term survival of breast cancer patients treated with DES suggest that high-dose estrogen treatment may be beneficial (6). We should not, therefore, dismiss this therapeutic strategy just because it flies in the face of our long-held beliefs. In addition, tumor regression was found to be dose-dependent in patients treated with DES, and at the present time there is no clinical evidence that low doses achieve the same results (6). Hence, hormone replacement therapy after selective estrogen receptor modulator therapy, as proposed by Jordan and his coworkers, may become an option after it is rigorously tested in a clinical setting.
We all agree that more research into the mechanism of hormone action on the control of cell proliferation and cell death is needed. However, as we proposed more than 20 years ago, in a 1980 editorial in this Journal (7), researchers in the field should also reassess their hypotheses, spell them out in detail, and resolve any contradictory results and interpretations of the data. Furthermore, rather than generating new data now and thinking later, we should reassess our thinking now, postulate potentially new hypotheses, and then carry out the appropriate experiments to test them. Indeed, philosophy does matter in medicine, not only in regard to the ethics of exposing patients to the unintended deleterious effects of overzealous treatments but also in regard to sound epistemology.
REFERENCES
1 Song RX, Mor G, Naftolin F, McPherson RA, Song J, Zhang Z, et al. Effect of long-term estrogen deprivation on apoptotic responses of breast cancer cells to 17beta-estradiol. J Natl Cancer Inst 2001;93:1714–23.
2 Yao K, Lee ES, Bentrem DJ, England G, MacGregor Schafer JI, O'Regan RM, et al. Antitumor action of physiological estradiol on tamoxifen-stimulated breast tumors grown in athymic mice. Clin Cancer Res 2000;6:2028–36.
3 Szelei J, Soto AM, Geck P, Desronvil M, Prechtl NV, Weill BC, et al. Identification of human estrogen-inducible transcripts that potentially mediate the apoptotic response in breast cancer. J Steroid Biochem Mol Biol 2000;72:89–102.[CrossRef][Web of Science][Medline]
4 Sonnenschein C, Szelei J, Nye TL, Soto AM. Control of cell proliferation of human breast MCF7 cells; serum and estrogen resistant variants. Oncol Res 1994;6:373–81.[Web of Science][Medline]
5 Fisher B, Dignam J, Bryant J, DeCillis A, Wickerjam DL, Wolmark N, et al. Five years versus more than 5 years of tamoxifen therapy for breast cancer patients with negative lymph nodes and estrogen receptor positive tumors. J Natl Cancer Inst 1996;88:1529–42.
6 Carter AC, Sedransk N, Kelley RM, Ansfield FJ, Ravdin RG, Talley RW. Diethylstilbestrol: recommended dosages for different categories of breast cancer patients. JAMA 1977;237:2079–85.
7 Sonnenschein C, Soto AM. But...are estrogens per se growth-promoting hormones? J Natl Cancer Inst 1980;64:211–5.[Web of Science][Medline]
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