Researchers At Norris Cotton Cancer Center Are Studying The Use Of Estrogen To Target Drug-resistant Breast Cancer

Todd Miller, PhD, and Nicole Traphagen, a PhD candidate in the Miller Laboratory, have found a method for long-term control of drug-resistant breast cancer growth in preclinical models by switching between estrogen and anti-estrogen therapies. The strategy is now in human clinical trials at Dartmouth's and Dartmouth-Hitchcock's Norris Cotton Cancer Center.

Researchers at Dartmouth and Dartmouth-Hitchcock’s Norris Cotton Cancer Center (NCCC) are hoping to make estrogen therapy a more accessible treatment option for advanced breast cancer patients.

Anti-estrogen treatments, which block growth signals from estrogen receptors in tumors, are effective treatments for estrogen receptors plus breast cancer. But it is common for breast tumors to become resistant to anti-estrogen treatments over time. Despite the fact that estrogen therapies are effective in some patients, estrogen therapy is rarely used. An ongoing clinical trial at NCCC will determine whether the strategy of cycling between estrogen therapy and anti-estrogen therapies is effective in human patients with advanced breast cancer.

The research team, led by molecular biologist Todd Miller, PhD, and Nicole Traphagen, a doctorate candidate in Miller’s Laboratory, found that in mice, cycling between estrogen treatment and anti-estrogen treatment at a specific point in time can dramatically increase the duration of tumor regression.

“Although we typically think of estrogen as feeding breast cancer growth, treatment with estrogen can actually induce tumor regression in some patients with breast tumors that have developed resistance to anti-estrogen treatments,” says Miller.

The team’s unconventional approach has exciting implications for breast cancer patients by suggesting the use of short-term estrogen therapy before anti-estrogen therapy resistance occurs, and then switching back to a more standard anti-estrogen therapy can better control tumor growth long-term. Traphagen and Miller have newly published their findings, entitled “High estrogen receptor alpha activation confers resistance to estrogen deprivation and is required for therapeutic response to estrogen in breast cancer,” in Oncogene.

“Tumors that initially respond to estrogen therapy eventually develop resistance to it by decreasing the amount of estrogen receptors in the tumor cells. Once these tumors become resistant to estrogen therapy, they can be successfully treated with anti-estrogen therapies,” says Traphagen. “This finding suggests that treatment with estrogen can re-sensitize patients’ tumors to anti-estrogen therapies, even if those tumors had previously acquired resistance to anti-estrogen treatments.”

Miller and Traphagen will also study the molecular characteristics of breast cells that respond to estrogen therapy. The goal is to use this information to predict and improve the selection of patients who may respond to estrogen therapy and inform the development of new drug combinations to optimize the anti-cancer effects of estrogen therapy.

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