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One's internal clock could be targeted to prevent or slow the progression of breast cancer

February 13, 2020

DUARTE, Calif. -- City of Hope scientists have identified an unlikely way to potentially prevent or slow the progression of aggressive breast cancer: target one's internal clock.

Often taken for granted, the circadian rhythm is gaining traction as a potential catalyst or brake for the onset of disease. For example, studies have shown that women who take frequent night shifts have disrupted internal clocks and increased risk of developing breast cancer. Now, City of Hope's David K. Ann, Ph.D., and his colleagues think they may have found a new role for the "clock gene": It is linked to triple-negative breast cancer, an aggressive form of the disease that often results in a poorer prognosis.

"We are the first to highlight the circadian protein BMAL1 as a tumor suppressor that interacts with the metabolism of prediabetic, obese people," said Ann, senior author of a new study and the Morgan & Helen Chu Dean's Chair of the Irell and Manella Graduate School of Biological Sciences at City of Hope. "Loss of BMAL1 in a prediabetic or obese environment gives breast cancer progression the competitive edge. This finding brings us one small step closer to the ability to provide more personalized breast cancer care based on an individual's genetics and lifestyle choices."

The retrospective study, to be published in the Feb. 21 issue of Cell Press' iScience, is a proof-of-concept investigation based on City of Hope's initial bioinformatics observations. Subsequent laboratory work used cell and mouse models to test the new hypothesis, which resulted in City of Hope scientists establishing a link among circadian rhythm, cell metabolism, breast cancer progression and nutritional health. Because obesity is a risk factor in many cancers, the City of Hope researchers next will look into how the clock gene may affect prediabetic, obese people with other major cancer types.

"The growing number of public databases in cancer genomics has afforded us the opportunity to generate hypotheses and validate discoveries for translational research," said Ching Ouyang, Ph.D., assistant research professor in the Center for Informatics and the Department of Computational and Quantitative Medicine at City of Hope, a world-renowned independent research and treatment center for cancer, diabetes and other life-threatening diseases. "City of Hope is a unique comprehensive cancer center that fosters collaboration. Physicians, researchers and data scientists find trends in clinical and laboratory data and work together to develop novel therapies."

In this study, the researchers found that obese, prediabetic mice without the BMAL1 protein derived from their clock gene experienced accelerated breast tumor growth compared to their lean animal model peers. Additionally, breast tumors spread to the lungs more quickly in obese mice, suggesting that BMAL1 is a novel target that can suppress tumor progression or metastasis in a prediabetic, obese environment.

Though more research is needed, Ann said that in the distant future, a doctor could determine an individual's BMAL1 levels, especially in tumors, as well as order blood work to understand the person's nutritional health. If BMAL1 levels are low and the individual is prediabetic or clinically obese, perhaps a not-yet-developed drug could be prescribed to increase BMAL1 levels. Additionally, the physician could advise the patient to reconsider her dietary habits.

"Although additional research is needed, something people can consider doing now is to eat smaller meals at more frequent intervals, decrease sugar intake, avoid high-fat foods and exercise more," Ann said.
Cassandra A. Ramos, Ph.D., is the first author of the study and a doctoral graduate of City of Hope's Irell & Manella Graduate School of Biological Sciences. She is now employed at the Center for Science in the Public Interest, a nonprofit that focuses on nutrition and food safety. Other key co-authors include City of Hope's Mark LaBarge, Ph.D., professor in the Department of Population Sciences, and Victoria L. Seewaldt, M.D., the Ruth Ziegler Chair in Population Sciences.

This research was supported by the National Institutes of Health's National Cancer Institute (R01CA220693), U.S. Department of Defense (BC141351) and a City of Hope Center for Cancer and Aging predoctoral fellowship (P30CA033572).

About City of Hope

City of Hope is an independent biomedical research and treatment center for cancer, diabetes and other life-threatening diseases. Founded in 1913, City of Hope is a leader in bone marrow transplantation and immunotherapy such as CAR T cell therapy. City of Hope's translational research and personalized treatment protocols advance care throughout the world. Human synthetic insulin and numerous breakthrough cancer drugs are based on technology developed at the institution. A National Cancer Institute-designated comprehensive cancer center and a founding member of the National Comprehensive Cancer Network, City of Hope is the highest ranked cancer hospital in the West, according to U.S. News & World Report's Best Hospitals: Specialty Ranking. Its main campus is located near Los Angeles, with additional locations throughout Southern California. For more information about City of Hope, follow us on Facebook, Twitter, YouTube or Instagram.

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