November 11, 2003
Estrogen Shrinks Some Breast Tumors
CHICAGO— Striking, paradoxical discoveries by Feinberg School of Medicine researchers 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.
The findings are described in two studies by V. Craig Jordan, PhD, and co-researchers at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University that were published in the Nov. 5 issue of the Journal of the National Cancer Institute.
Dr. Jordan is the Diana, Princess of Wales, Professor of Cancer Research; professor of molecular pharmacology and biological chemistry at the medical school; and director of the Lynn Sage Breast Cancer Research Program at the Cancer Center.
Tamoxifen is a selective estrogen receptor modulator (SERM) used to treat estrogen receptor-positive breast cancers and prevent recurrence of the disease. However, tamoxifen loses effectiveness after five years and can subsequently stimulate breast cancer growth. New endocrine therapies, such as aromatase inhibitors and the antiestrogen fulvestrant, are used to boost the effects of tamoxifen, although some studies suggest that low levels of estrogen may also inhibit the growth of tamoxifen-stimulated breast tumors.
Clodia Osipo, PhD, who is lead author on the tamoxifen article; Dr. Jordan; and Cancer Center colleagues examined the effect of tamoxifen, the estrogen estradiol, and fulvestrant, both alone and in various combinations, in a laboratory 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 cell suicide, or apoptosis, through decreased expression of the antiapoptotic factors Her2/neu and NF-(kappa)B and increased expression of the death receptor protein Fas, with regulates apoptosis.
Combined treatment with fulvestrant plus estadiol unexpectedly promoted the growth of tamoxifen-stimulated breast tumors, suggesting that use of fulvestrant in patients with sufficient levels of circulating estrogen may actually stimulate tumor growth.
In the second study, Hong Liu, MD, PhD; Dr. Jordan, and cancer center co-researchers 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 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-(kappa)B activity, an increase in the expression of the Fas protein, and an increase in apoptosis.
The researchers also 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 five 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,” Dr. Jordan said.
“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 women with estrogen before re-instituting estrogen-deprivation therapy may benefit certain women,” he said.
