The Estrogen Paradox

Hormone that promotes breast cancer growth may eventually kill it

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By
HealthDay Reporter

WEDNESDAY, Nov. 5, 2003 (HealthDayNews) -- Estrogen, the hormone that fuels the development of hormone-dependent breast cancers, may later cause those same cancer cells to commit suicide.

That's the conclusion of two new studies appearing in the Nov. 5 issue of the Journal of the National Cancer Institute.

Researchers found that when breast cancer tumors develop a resistance to the anticancer drugs tamoxifen and raloxifene, low levels of estrogen -- as low as those found in postmenopausal women -- may actually make the tumors shrink.

Tamoxifen is a selective estrogen receptor modulator (SERM), a type of drug used to treat and prevent breast cancer. Raloxifene is a SERM, but it is also used to prevent osteoporosis. The problem with these medications is that cancer cells eventually develop a resistance to them, and then SERMs can even begin to promote cancer cell growth.

"Estrogen goes through a totally unanticipated change," says study author Dr. V. Craig Jordan, director of the Lynn Sage Comprehensive Breast Center at the Robert H. Lurie Comprehensive Cancer Center at Northwestern University in Chicago. "Estrogen, rather than being a driving force when we stop SERMs, binds to estrogen receptors. The estrogen receptor now recognizes that this is an evil environment and switches a switch that orders the cell to undergo a death sequence. This is a natural process that causes them to commit suicide."

In 2003, approximately 211,300 women and 1,300 men will be diagnosed with breast cancer in the United States, the American Cancer Society (ACS) estimates. There are currently about 2 million women living with breast cancer, according to the ACS.

While the incidence of breast cancer is rising slightly -- by about 2 percent every year -- the death rates from the disease are declining. The ACS estimates that nearly 40,000 women and 400 men will die from breast cancer in 2003.

In one experiment, Jordan and his colleagues looked at how effective tamoxifen, estradiol (an estrogen) and fulvestrant (an anti-estrogen) were in treating a mouse model of human tamoxifen-stimulated breast cancer. They studied the treatments alone, and in various combinations.

They found low levels of estradiol made the breast tumors shrink, while tamoxifen alone or estradiol combined with fulvestrant had the opposite effect. Jordan says this is an important finding because fulvestrant is often used in women who have grown resistant to tamoxifen. However, if these findings hold true in humans, giving fulvestrant to a woman who has significant enough estrogen levels may actually promote tumor growth.

In the other study, the researchers looked at how low doses of estradiol would affect raloxifene-resistant cancer cells. The researchers treated raloxifene-resistant breast cancer cells in culture with estradiol for 12 to 24 days.

They found that cells resistant to raloxifene were also resistant to tamoxifen. But more important, the researchers discovered that estradiol inhibited cell growth in these experiments.

In both studies, the researchers believe estrogen affected the cancer cells by causing them to express a death receptor protein, and decreased their expression of proteins that inhibit cell suicide.

"That we have a natural signal mechanism to kill is totally unanticipated," says Jordan, who believes this finding may be as big a breakthrough as tamoxifen was. "What we want to do is find the trigger that kills the cancer cells. Then, if we can find the trigger, the question becomes, can we apply it to all cancers?"

"Dr. Jordan and his group have suggested that the difference in these cells and how they behave depends on the hormonal milieu in which they see themselves," explains Dr. Daniel Hayes, clinical director of the breast oncology program at the University of Michigan Comprehensive Cancer Center in Ann Arbor. Hayes also authored an editorial about the studies in the same issue of the Journal of the National Cancer Institute.

Hayes points out these findings have no immediate clinical significance and won't change the way patients are treated right now.

Jordan says he and his team will be starting a whole new series of experiments to try to find out what the trigger is, and that they're working on establishing clinical trials. He says the unexpected findings have given the researchers a new place to focus their research attention.

More information

To learn more about breast cancer, visit The Susan G. Komen Breast Cancer Foundation or the American Cancer Society.

SOURCES: V. Craig Jordan, Ph.D., D.Sc., Diana Princess of Wales professor, cancer research, and director, Lynn Sage Comprehensive Breast Center, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago; Daniel Hayes, M.D., clinical director, breast oncology program, University of Michigan Comprehensive Cancer Center, Ann Arbor; Nov. 5, 2003, Journal of the National Cancer Institute

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