News Release

Targeting drug-resistant breast cancer with estrogen

Dartmouth researchers achieve better long-term control of drug-resistant breast cancer growth in mice by switching between estrogen and anti-estrogen therapies. A new clinical trial will inform which patients may benefit from this strategy

Peer-Reviewed Publication

Dartmouth-Hitchcock Medical Center

Todd Miller, PhD, and Nicole Traphagen in the Miller laboratory

image: Todd Miller, PhD (left), 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. view more 

Credit: Mark Washburn

LEBANON, NH - Researchers at Dartmouth's and Dartmouth-Hitchcock's Norris Cotton Cancer Center (NCCC) hope to make estrogen therapy a more accessible treatment option for breast cancer patients who could benefit from it. Anti-estrogen treatments, which block growth signals from estrogen receptors (ER) in tumors, are effective treatments for ER+ breast cancer. But it is common for breast tumors to become resistant to anti-estrogen treatments over time. The research team, led by molecular biologist Todd Miller, PhD, and Nicole Traphagen, a PhD candidate in the Miller 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.

The team's unconventional approach has exciting implications for breast cancer patients by suggesting that treating short-term with estrogen 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.

"Although we typically think of estrogens as feeding breast cancer growth, treatment with estrogens can actually induce tumor regression in some patients with anti-estrogen resistant breast tumors," says Miller. Despite the fact that estrogen treatment is effective in some patients, estrogen therapy is rarely used. An ongoing clinical trial at NCCC (POLLY; NCT0218875) will determine whether the strategy of cycling between estrogen therapy and anti-estrogen therapies is effective in human patients with advanced breast cancer.

"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 selection of patients who may respond to estrogen therapy and inform development of new drug combinations to optimize the anti-cancer effects of estrogen therapy.


Todd W. Miller, PhD, is Co-Director of the Cancer Biology and Therapeutics Research Program and of the Molecular Tumor Board at Dartmouth's and Dartmouth-Hitchcock's Norris Cotton Cancer Center (NCCC), Scientific Director of NCCC's Comprehensive Breast Program, and Associate Professor of Molecular and Systems Biology at the Geisel School of Medicine at Dartmouth. Research in the Miller laboratory focuses on the identification of cancer signaling pathways and the development of targeted therapies for breast and other cancers.

About Norris Cotton Cancer Center

Norris Cotton Cancer Center, located on the campus of Dartmouth-Hitchcock Medical Center (DHMC) in Lebanon, NH, combines advanced cancer research at Dartmouth College's Geisel School of Medicine in Hanover, NH with the highest level of high-quality, innovative, personalized, and compassionate patient-centered cancer care at DHMC, as well as at regional, multi-disciplinary locations and partner hospitals throughout NH and VT. NCCC is one of only 51 centers nationwide to earn the National Cancer Institute's prestigious "Comprehensive Cancer Center" designation, the result of an outstanding collaboration between DHMC, New Hampshire's only academic medical center, and Dartmouth College. Now entering its fifth decade, NCCC remains committed to excellence, outreach and education, and strives to prevent and cure cancer, enhance survivorship and to promote cancer health equity through its pioneering interdisciplinary research. Each year the NCCC schedules 61,000 appointments seeing nearly 4,000 newly diagnosed patients, and currently offers its patients more than 100 active clinical trials.

About Dartmouth-Hitchcock Health

Dartmouth-Hitchcock Health (D-HH), New Hampshire's only academic health system and the state's largest private employer, serves a population of 1.9 million across northern New England. D-H provides access to more than 2,000 providers in almost every area of medicine, delivering care at its flagship hospital, Dartmouth-Hitchcock Medical Center (DHMC) in Lebanon, NH. DHMC was named again in 2020 as the #1 hospital in New Hampshire by U.S. News & World Report, and recognized for high performance in 9 clinical specialties and procedures. Dartmouth-Hitchcock also includes the Norris Cotton Cancer Center, one of only 51 NCI-designated Comprehensive Cancer Centers in the nation; the Children's Hospital at Dartmouth-Hitchcock, the state's only children's hospital; affiliated member hospitals in Lebanon, Keene, and New London, NH, and Windsor, VT, and Visiting Nurse and Hospice for Vermont and New Hampshire; and 24 Dartmouth-Hitchcock clinics that provide ambulatory services across New Hampshire and Vermont. The D-H system trains nearly 400 residents and fellows annually, and performs world-class research, in partnership with the Geisel School of Medicine at Dartmouth and the White River Junction VA Medical Center in White River Junction, VT.

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