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David Baxter PhD

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Clearing Up Confusion About Estrogen Therapy and Breast Cancer
by Roxanne Nelson, Medscape
April 22, 2011

The recent finding that estrogen-alone therapy may actually reduce the incidence of breast cancer has created some degree of confusion in the mainstream media. For example, in her comments about the study, New York Times columnist Gail Collins asked the medical profession to "please make up its mind."

However, an editorial published online April 10 in Cancer Prevention Research suggests that these findings are neither perplexing nor contradictory, but are consistent with the underlying biology of estrogen and breast cancer, if properly observed.

Specifically, the editorialists note that even though it seems paradoxical because estrogen is recognized to stimulate breast cancer growth, laboratory data support a mechanism of estrogen-induced apoptosis under correct environmental circumstances. Namely, apoptosis may be induced by exogenous estrogen when there has been a period of long-term natural estrogen deprivation, according to coeditorialist V. Craig Jordan, PhD, DSc, FMedSci.

Such a circumstance happens in the bodies of women who, after losing estrogens naturally for the protracted time leading up to menopause, use estrogen supplements, said Dr. Jordan, scientific director and vice chairman of oncology at the Lombardi Comprehensive Cancer Center of Georgetown University, Washington, DC.

Confusion Over Data
As previously reported by Medscape Medical News, at a 10.7-year follow-up of postmenopausal women with prior hysterectomy, the risk for breast cancer was reduced among those women receiving estrogen therapy alone compared with placebo, even after cessation of the treatment. The study, which was published in the April 6 issue of JAMA, drew its data from the Women's Health Initiative Estrogen-Alone Trial (JAMA. 2011;305:1305-1314, 1354-1355).

The confusion stems from previous findings of the Women's Health Initiative, when their trial of combination estrogen plus progestin was stopped in July 2002 because of an increased risk for breast cancer and stroke. Two years later, the Estrogen-Alone segment was halted.

"The Women's Health Initiative Estrogen-Alone Trial was stopped early after a mean of 7.1 years of follow-up because of an increased risk of stroke and little likelihood of altering the balance of risk to benefit by the planned trial termination date," write the authors of the JAMA study, led by Andrea Z. LaCroix, PhD, from the Fred Hutchinson Cancer Research Center in Seattle, Washington.

However, they note that the postintervention data for women who had used estrogen for a median of 5.9 years were not associated with an increased or decreased risk for heart disease, deep vein thrombosis, stroke, hip fracture, colorectal cancer, or total mortality. "A decreased risk of breast cancer persisted," they write.

Long-Term Estrogen Deprivation Is Key
"The Women's Health Initiative Estrogen-Alone Trial demonstrated a decrease in breast cancer during treatment, until 5 years after treatment," Dr. Jordan told Medscape Medical News in an interview.

He pointed out that even though estrogen can be carcinogenic in breast tissue, the results of this recent study are consistent with laboratory evidence that physiologic estrogen can cause apoptosis in breast cancer cells after long-term estrogen deprivation.

"We know that if breast cancer cells are deprived of estrogen, the majority of the cells die off, and then cells come back that can grow with a minimum of estrogen," said Dr. Jordan, who has frequently been dubbed "the father of tamoxifen therapy" by the media, as his team was the first to discover the breast cancer prevention properties of tamoxifen.

"The same is true for when we treat with antihormone therapy," he continued. "The cells stop growing, and after a long time become resistant. What we know is, if you put estrogen back after you stop the therapy, the cells die. The estrogen kills the cells."

The onset of menopause "switches" off the ovary and starves the breast of hormones, and in turn, the lack of circulating estrogen now produces an estrogen-withdrawal-like effect. "So the occult breast cancer cells that are already in the breast now start to learn to grow very slowly, with very little available estrogen," said Dr. Jordan. "When the woman then uses estrogen replacement therapy, say at about age 60 or older, it does the exactly the same as we see with the cells in the laboratory ? it causes those microcells in the breast to die off.

"And that is why we saw fewer breast cancers in that trial," he noted.

Dr. Jordan further explained that although it is true that estrogen will stimulate growth of breast cancer cells in the right environment, "it's similar to Darwinian evolution."

"In a nice environment, where there a lot of resources, everything grows," he pointed out. "There is unlimited fuel for the fire. When the environment changes, and you take the estrogen away, the population changes, and the weak die off."

Although the cancer cells need estrogen to survive, a small population of the cells is able to grow in the absence of the hormone. These breast cancer cell populations adapt to estrogen deprivation, but are dynamic, and their resistance to estrogen deprivation evolves over time. In the case of this particular trial, it was 5 years.

The evolution of resistance to estrogen deprivation causes a reconfiguration of cellular survival pathways, which in turn exposes a vulnerability of breast cancer cell survival. "These cells are hardy, but vulnerable," said Dr. Jordan. "And they are vulnerable when they are growing slowly."

The cells choose to die through a natural process when they are reexposed to pharmacologic or physiologic estrogen. Thus, estrogen causes apoptosis and does not act as a survival signal. "It's like an old VW," he explained. "If you give it jet fuel instead of normal gasoline, it will go boom, and that's like these cells getting estrogen."

The authors have disclosed no relevant financial relationships. The editorial was supported by the following grants to Dr. Jordan: Department of Defense Breast Program, the Susan G. Komen for the Cure Foundation, and the Lombardi Comprehensive Cancer Center Support Grant from the National Cancer Institute.

Cancer Prev Res. Published online April 10, 2011. Full text
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