Estrogen has antitumor activity in hormone therapy-resistant breast tumors

December 31, 2000

A pair of studies in the November 5 issue of the Journal of the National Cancer Institute suggest that low levels of estrogen--the same hormone that promotes breast cancer in its early stages--can shrink breast tumors that have developed resistance to the drugs tamoxifen and raloxifene.

Tamoxifen is a selective estrogen receptor modulator (SERM) used to treat estrogen receptor-positive breast cancers and prevent recurrence of the disease. However, tamoxifen often loses effectiveness over time and can subsequently stimulate breast cancer growth. New endocrine therapies, such as aromatase inhibitors and the antiestrogen fulvestrant, are being are used to augment the effects of tamoxifen, although some studies are suggesting that low levels of estrogen may also inhibit the growth of tamoxifen-stimulated breast tumors.

Clodia Osipo, Ph.D., and V. Craig Jordan, Ph.D., D.Sc., of the Robert H. Lurie Comprehensive Cancer Center at Northwestern University in Chicago, and their colleagues examined the effect of tamoxifen, the estrogen estradiol, and fulvestrant, both alone and in various combinations, in a mouse model of tamoxifen-stimulated human breast cancer.

The researchers found that low levels of estradiol caused tamoxifen-resistant breast tumors to regress, apparently by increasing apoptosis (cell suicide) through decreased expression of Her2/neu and NF-κB, two factors that inhibit apoptosis, and increased expression of the death receptor protein Fas, which regulates apoptosis.

Combined treatment with fulvestrant plus estradiol unexpectedly promoted the growth of tamoxifen-stimulated breast tumors, suggesting that the use of fulvestrant in patients with sufficient levels of circulating estrogen may actually stimulate tumor growth.

In the second study, Hong Liu, M.D., Ph.D., of the Robert H. Lurie Comprehensive Cancer Center, Jordan, and their colleagues examined whether low doses of estradiol would also have an effect on raloxifene-resistant breast cancer cells. Widespread use of the SERM raloxifene for the prevention of osteoporosis has raised concerns that such women may eventually develop breast cancers that are resistant to raloxifene.

Treatment of cultured raloxifene-resistant breast cancer cells with estradiol for 12 to 24 days inhibited cell growth compared with untreated control cells. Estradiol treatment also caused a decrease in NF-κB activity, an increase in the expression of the Fas protein, and an increase in apoptosis. The researchers found that raloxifene-resistant cells were also resistant to tamoxifen, suggesting that tamoxifen would not be effective against breast cancers that are resistant to raloxifene. In addition, mice with drug-resistant tumors experienced tumor shrinkage after 5 weeks of estradiol treatment.

Together, these studies "suggest that it is possible for a patient's own estrogen to act as an anticancer agent in SERM-resistant breast cancers," the authors write. "Clearly, a clinical strategy to use an aromatase inhibitor after SERM resistance may have some short-term benefit for patients, but it is possible that a novel strategy of briefly treating patients with estrogen before re-instituting estrogen-deprivation therapy may benefit certain women."

In an accompanying editorial, Daniel F. Hayes, M.D., of the University of Michigan Comprehensive Cancer Center in Ann Arbor, says that the findings "are provocative" and raise the question of whether the role of the old standard estrogen should be reexamined in breast cancer therapy. Although the findings need to be confirmed in additional studies, a better understanding of estrogen and the estrogen receptor may permit the development of a new use for estrogen therapy, he says.
Contact: Elizabeth Crown, Northwestern University, 312-503-8928,

Editorial: Shelley Zalewski, University of Michigan Comprehensive Cancer Center, 734-936-9584,

Liu H, Lee E, Gajdos C, Pearce ST, Chen B, Osipo C, et al. Apoptotic action of 17â -estradiol in raloxifene-resistant MCF-7 cells in vitro and in vivo. J Natl Cancer Inst 2003;95:1586-97.

Osipo C, Gajdos C, Liu H, Chen B, Jordan VC. Paradoxical action of fulvestrant in estradiol-induced regression of tamoxifen-stimulated breast cancer. J Natl Cancer Inst 2003;95:1597-1608.

Hayes DF. Playing the old piano: Another tune for endocrine therapy? J Natl Cancer Inst 2003;95:1565-7.

Note: The Journal of the National Cancer Institute is published by Oxford University Press and is not affiliated with the National Cancer Institute. Attribution to the Journal of the National Cancer Institute is requested in all news coverage.

Journal of the National Cancer Institute

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