Affiliations of authors: R. X.-D. Song, R. J. Santen, Department of Internal Medicine, University of Virginia, Charlottesville; L. M. Berstein, Laboratory of Oncoendocrinology, Petrov Research Institute of Oncology, St. Petersburg, Russia.
Correspondence to: Robert X.-D. Song, M.D., Ph.D., University of Virginia Health Sciences Center, School of Medicine, Department of Internal Medicine, Jordan Hall, Charlottesville, VA 22908 (e-mail: rs5wf{at}virginia.edu).
Jordan et al. suggest reconsideration of our observations regarding estradiol and apoptosis from a broader perspective. We agree with their comment and with the need to devise practical therapeutic methods to exploit the principles of adaptability uncovered in our studies (3,4). A common theme suggested by our experiments (1,2), and by those of both the Jordan and the Soto/Sonnenschein laboratories (3,4), is that breast cancer cells change their responsiveness when subjected to various hormonal therapies. MCF-7 breast cancer xenografts initially respond to tamoxifen and raloxifene as estrogen antagonists but upon continued exposure, as estrogen agonists. Prolonged estradiol deprivation in vitro causes hypersensitivity to both the proliferative and apoptotic effects of estradiol (1,2). Breast cancer cells possess a high degree of plasticity, which allows them to adapt via epigenetic changes to endocrine therapies that are initially effective, by becoming resistant to those therapies later.
Jordan et al. suggest that clinicians try to leverage these concepts into more effective therapies for patients. They argue that the pro-apoptotic effects of estrogen have now been demonstrated in several model systems and may, therefore, be a generalizable phenomenon. We agree with this assertion but suggest that the more global concept of "adaptive hypersensitivity" also be introduced (5). This term describes the ability of breast cancer cells to adapt to various therapies designed to block estrogen action by becoming hypersensitive to the effects of femtomolar to picomolar concentrations of estrogen on both proliferation and apoptosis. We would also extend the comments of Jordan et al. by suggesting that adaptive hypersensitivity could be the conceptual basis on which to design cyclic treatment strategies. Theoretically, these strategies might involve the use of aromatase inhibitors or selective estrogen receptor modulators (SERMs) for the period of time necessary to sensitize cells to the pro-apoptotic effects of estrogen. At that point, the aromatase inhibitor or the SERMs could be stopped and then followed by administration of low doses of estrogen. High doses, such as those used historically with diethylstilbestrol (DES) treatment (6), would probably not be needed. Because the adaptive process of the cancer cells might then cause subsequent resistance to the pro-apoptotic effects of estrogen, patients would need to be switched back to an aromatase inhibitor or SERM treatment at a later date. Several cycles of estrogen followed by an antiestrogen or an aromatase inhibitor might then provide optimal efficacy. This new strategy may potentially delay or abrogate resistance to hormonal therapies in women with breast cancer.
The concepts underlying this new therapeutic approach remain to be validated. However, clinical data suggest its feasibility. For example, women with metastatic breast cancer who were crossed over from tamoxifen to DES respond to rechallenge with estrogen (6). In addition, women who were treated initially with DES also respond to tamoxifen when crossed over to that agent (7). Our concepts regarding adaptive hypersensitivity would be congruent with the suggestion of Jordan et al.that is, that low-dose estrogen could ultimately aid patient survival if used in the proper setting. We envision that the design of these new therapeutic strategies would involve cycles of "hormone ablative" followed by "hormone additive" therapy. The goal, therefore, would be to retard development of resistance to either of these therapies and to ultimately aid patient survival. The emerging data on the pro-apoptotic effects of estradiol support the validity of such an approach and the initiation of preclinical trials of the cyclic therapy described above.
NOTES
L. M. Berstein is a recipient of an International Union Against Cancer (UICC) AstraZeneca Translational Cancer Research Fellowship (TCRF).
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;93:171423.
2 Masamura S, Santner SJ, Heitjan DF, Santen RJ. Estrogen deprivation causes estradiol hypersensitivity in human cancer cells. J Clin Endocrinol Metab 1995;80:291825.[Abstract]
3 Soto AM, Sonnenschein C. The two faces of Janus: sex steroids as mediators of both cell proliferation and cell death. J Natl Cancer Inst 2001;93:16735.
4 O'Regan RM, Gajdos C, Dardes RC, De Los Reyes A, Park W, Rademaker AW, et al. Effects of raloxifene after tamoxifen on breast and endometrial tumor growth in athymic mice. J Natl Cancer Inst 2002;94:27483.
5 Santen R, Jeng MH, Wang JP, Song R, Masamura S, McPherson R, et al. Adaptive hypersensitivity to estradiol: potential mechanism for secondary hormonal responses in breast cancer patients. J Steroid Biochem Mol Biol 2001;79:11525.[Medline]
6 Peethambaram PP, Ingle JN, Suman VJ, Hartmann LC, Loprinzi CL. Randomized trial of diethylstilbestrol vs. tamoxifen in postmenopausal women with metastatic breast cancer. An updated analysis. Breast Cancer Res Treat 1999;54:11722.[Medline]
7 Gockerman JP, Spremulli EN, Raney M, Logan T. Randomized comparison of tamoxifen versus diethylstilbestrol in estrogen receptor-positive or -unknown metastatic breast cancer: a Southeastern Cancer Study Group trial. Cancer Treat Rep 1986;70:1199203.[Medline]
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