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Miller School Researcher Leads Pivotal Breast Cancer Study

For years, the most common type of breast cancer, known as estrogen receptor positive, or ER-positive, has been the most treatable, usually with antiestrogen hormone therapies that block the growth-promoting effects of estrogen.

But a seminal study designed and coordinated by Tan A. Ince, M.D., Ph.D., associate professor of pathology, member of the Braman Family Breast Cancer Institute at Sylvester, and director of the Tumor Stem Cell Division at the Interdisciplinary Stem Cell Institute at the Miller School of Medicine, has pinpointed a protein that, when expressed in high levels in ER-positive tumors, is linked to a doubling of mortality in ER-positive patients.

To be published online this week in the Proceedings of the National Academy of Sciences (PNAS), the finding that high levels of heat shock factor 1 (HSF1) in breast cancers is associated with significantly reduced disease survival, particularly for patients with ER-positive tumors, may have significant future application in guiding clinicians to the optimal treatment for ER-positive breast cancer. The researchers found high HSF1 levels in nearly 30 percent of the ER-positive patients studied. Today, ER-positive patients are often treated with both chemotherapy and anti-estrogen drugs. These findings also could lead to the development of a new class of drugs that specifically target HSF1, which could improve survival in this subset of patients.

“In summary, we demonstrate that HSF1 is associated with reduced survival in breast cancer patients, particularly among those with ER-positive disease. Future efforts to evaluate HSF1 as a prognostic factor for routine clinical management of ER-positive patients are warranted. The findings support efforts to identify drugs that specifically target HSF1 function,’’ Ince and his collaborators from the Whitehead Institute for Biomedical Research at MIT, Harvard Medical School/Brigham and Women’s Hospital, and the Nurses’ Health Study concluded in the study.

HSF1 is the master regulator of the entire family of heat shock proteins, which help cells cope with heat and many other stressors, particularly metabolic stress. Ince and his collaborators, whose work was supported by The Breast Cancer Research Foundation founded by Evelyn Lauder in New York, are the first to demonstrate HSF1’s potential as a prognostic marker in breast cancer.

The researchers previously showed that HSF1 increased the growth and survival of a type of breast cancer cell that forms aggressive tumors in mice. This led them to hypothesize that HSF1 is expressed in a subset of breast cancers and associated with poor survival. To test the hypothesis, they examined HSF1 levels in breast cancers from 1,841 participants in the Nurses’ Health Study. Established at Harvard in 1976, the study is one of the largest and longest running investigations of factors that influence women’s health, and includes 239,000 nurse participants.

The significant size of the breast cancer cohort, and the ability to track their long-term outcomes over many years enabled Ince and his team to pinpoint a clear link between the master regulator of heat shock proteins and mortality in the ER-positive group.

“In nearly 1,850 breast cancer patients, we found that if a tumor expresses HSF1 at high levels, mortality went up 1.5 times,’’ Ince said. “When we looked specifically at the ER-positive tumor subset, we found that high HSF1 expression actually correlated with a doubling of mortality in that group. These high HSF1 tumors accounted for almost one third of the patients with ER-positive tumors. In order to confirm these results, we also looked at a second group of breast cancers and found that increased HSF1 mRNA correlates with a nearly three-fold increase in mortality in the ER-positive group.”

The investigators did not find that HSF1 played a major role in increasing mortality in patients with the two other major classes of breast cancer tumors, HER2-positive and Triple Negative. But since those tumors are less common and the nurses’ study includes fewer HER2-positive and Triple Negative participants, Ince said they may not have had enough patients to detect an effect.

“Our findings are striking for the ER-positive group,’’ Ince said of the study, which he initiated while at Harvard and Whitehead and continued at the Miller School after joining UM in September 2010. “The relevance of HSF1 to other types of breast cancer will require further study.”

Ince hopes the PNAS study will lead to a number of other studies, first and foremost a clinical trial to test whether survival rates improve when ER-positive patients who express HSF1 receive additional, longer or higher doses of treatment. If so, he foresees the day when HSF1 will become a therapeutic marker, or target, for a new class of drugs designed to inhibit HSF1 in breast tumors, and possibly other types of cancer.

That’s what happened, he notes, with HER2-positive tumors. Initially, the human epidermal growth factor receptor 2 (HER2) protein was a prognostic marker indicating a worse outcome for HER2-positive patients, but this finding led to development of the drug traztuzumab, also known as Herceptin, which blocks HER2. Now HER2-positive breast cancers have a much better outcome because HER2 can be targeted therapeutically.

“Science is littered with false hopes, and we still need independent follow-up studies to confirm our results and give us greater confidence in our conclusions, but they are as remarkable as anything that I had hoped for so far,” Ince said. “Our work points to a better way of targeting heat shock proteins as a family, and, if that’s correct, I can see a day when patients with ER-positive tumors who test positive for HSF1 receive a drug that specifically targets HSF1.’’

Ince’s principal collaborators on the PNAS study include first author Sandro Santagata, M.D., Ph.D., of Harvard Medical School, Brigham and Women’s Hospital and the Whitehead Institute for Biomedical Research; heat shock protein expert Susan Lindquist, Ph.D., of the Whitehead Institute and Howard Hughes Medical Institute at MIT; and Rulla M. Tamimi, Sc.D., of Harvard Medical School and Brigham and Women’s Hospital, who supervises the Nurses’ Health Study.

Titled “High levels of nuclear HSF1 are associated with poor prognosis in breast cancer,” the study is slated for print publication at a future undetermined date.

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