Affiliations of authors: V. C. Jordan, H. Lui, R. Dardes, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL.
Correspondence to: V. Craig Jordan, OBE, Ph.D., D.Sc., Robert H. Lurie Comprehensive Cancer Center of Northwestern University, 303 E. Chicago Ave., Olson Pavilion Rm. 8258, Chicago, IL 60611 (e-mail: vcjordan{at}northwestern.edu).
The recent excellent paper by Song et al. (1) and the accompanying editorial (2) deserve a broader perspective than that presented by the observations with estrogen-deprived MCF-7 cell lines in vitro. Song et al. (1) state that their data on the apoptotic effects of high-dose estrogen could provide insights into the mechanism of pharmacologic estrogen used to treat breast cancer some 2030 years ago. Estrogen-deprived cells actually become supersensitized to physiologic concentrations of estrogen (1010 109 M). This range (27272 pg/mL) is equivalent to that observed in the circulation of perimenopausal and premenopausal women.
Although the goal of discovering a mechanism for estrogen-induced apoptosis when used as a therapy is valid, important additional applications of the new knowledge should be pursued. For example, breast cancer patients are currently being exposed to long-term estrogen withdrawal with aromatase inhibitors and selective estrogen receptor modulators (SERMs). The two SERMs, tamoxifen and raloxifene, are administered for at least 5 years for the treatment and prevention of breast cancer and osteoporosis, respectively (3). The existence of resistance to tamoxifen and raloxifene is evidenced by SERM-stimulated tumor growth in vivo (46). In the case of tamoxifen resistance, MCF-7 tumors grow initially in response to both tamoxifen and estrogen, but after 5 years in a tamoxifen-treated environment, the tumors become supersensitive to the tumoricidal actions of physiologic estrogen (5) and regress rapidly. Indeed, it has been suggested (5) that a woman's own estrogen may be responsible for the persistent survival benefit that patients enjoy following 5 years of adjuvant tamoxifen therapy (5). Interestingly, in the laboratory some tumors regrow in the estrogen environment, and these tumors again respond to tamoxifen as an antiestrogen (5). A subset of breast cancer patients will also have a response to tamoxifen following adjuvant tamoxifen therapy.
The mechanism of low-dose estrogen-induced apoptosis is unknown, but because the accumulating evidence suggests that it is a general mechanism of action for multiple types of endocrine therapy (1,47), this may be an important area for future research. Recently, we observed that T47D breast cancer cells stably transfected with protein kinase C (PKC)- grow spontaneously in athymic mice (7) but that a low concentration of estradiol causes rapid regression of the tumor. The increased activity of the PKC phosphorylation cascade might supersensitize cells to the tumoricidal effects of estrogen.
We wish to echo the conclusion of Soto and Sonnenschein in their editorial (2)that estrogen-induced apoptosis may be caused by a complex interaction of estrogen with both the cancer cell and the stromal component of the tumor. We uniformly observe estrogen-stimulated growth of breast cancer cells in vitro, but when the cells are transplanted into animals, profound reductions in tumor size occur (7), with circulating estrogen concentrations in the 4060 pg/mL rangethat is, dramatically lower concentrations than are routinely found in premenopausal women. The fact that in vivo systems amplify the tumoricidal action of estrogen is good news for the clinical application of the knowledge, but the finding provides a complex paradigm to address precise mechanisms in the laboratory.
The laboratory demonstration of the tumoricidal actions of physiologic levels of estrogen should not persuade clinicians to rechallenge their patients with high-dose estrogen after safer endocrine therapies have been exhausted. Rather, we suggest that clinicians should think about ways to test how the emerging new knowledge about breast cancer sensitization to low-dose estrogen could ultimately aid patient survival. Although we appreciate that the wisdom of the time is that estrogen is bad and that it is fashionable to be "antiestrogenic," we suggest that an integration of the concept of lower-dose estrogen after SERM therapy be evaluated, to improve both response and quality of life. Hormone replacement therapy after SERM treatment may have unexpected benefits.
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 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.
3 Jordan VC, Gapstur S, Morrow, M. Selective estrogen receptor modulation to reduce breast cancer risk, osteoporosis, and coronary heart disease. J Natl Cancer Inst 2001;93:144957.
4 Dardes RC, Liu H, Gajdos C, O'Regan R, de los Reyes A, Jordan VC. Raloxifene stimulated endometrial cancer grown in athymic mice: cross resistance with ICI182,780 and antitumor action of estradiol [abstract 447]. Breast Cancer Res Treat 2001;69:288.
5 Yao K, Lee ES, Bentrem DJ, England G, 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;6:202836.
6 Liu H, Lee ES, de Los Reyes A, Jordan VC. Antitumor action of estradiol on estrogen-deprived or raloxifene-resistant human breast cancer cells [abstract 573]. Breast Cancer Res Treat 2000;64:134.
7 Chisamore MJ, Ahmed Y, Bentrem D, Jordan VC, Tonetti DA. A novel antitumor effect of estradiol in athymic mice injected with a T47D breast cancer cell line overexpressing protein kinase c alpha. Clin Cancer Res 2001;7:315665.
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