Discovery of an epigenetic regulator of tumorigenesis suggests new strategies against
NEW YORK, NY – June 23, 2016 – Mount Sinai scientists have identified a previously unknown mechanism by which a protein called CBX8 promotes tumor growth in the most lethal forms of breast cancer. The study, published today in the journal Cell Reports, underscores the need for cancer researchers to pay more attention to "epigenetic" factors, meaning chemical and biological processes that control gene expression without changing the underlying DNA sequence of the cells that are running amok.
One out of eight women in the United States is diagnosed with breast cancer. A subset of them are tragically afflicted with forms of the illness that don't respond to any traditional or targeted treatments. For years, a growing body of evidence has suggested that epigenetic factors play a role in oncogenic (cancer-promoting) cell signaling pathways and may explain why some cancers are so resistant to treatment. But the mechanisms are poorly understood–in part, because focused epigenetic investigations in oncology are still relatively new.
"Looking beyond traditional genetics is critical because we have learned that epigenetic factors, the protein CBX8 in this case, are required for tumorigenesis and malignant phenotypes of breast cancer cells," said Emily Bernstein, PhD, Associate Professor of Oncological Sciences and Dermatology at the Icahn School of Medicine at Mount Sinai. "We also know that CBX8 is overexpressed in primary breast tumors, and that high CBX8 expression in patients correlates with poor outcome."
CBX8 maintains a stem cell-like gene expression pattern in breast cancer cells, and in particular, an important pathway called Notch signaling. This cellular pathway is important for both mammary development and tumorigenesis, and when CBX8 is dysregulated, the result is uncontrolled cell growth. "It appears that CBX8 is hijacked in breast cancer cells," said Chi-Yeh (Jay) Chung, a PhD candidate at the Icahn School of Medicine and lead author of the new study. "Our genomic analysis revealed, both in mouse and human breast cancer cell lines, that CBX8 promotes the Notch signaling pathway."
In breast cancer, the "upregulation" of Notch signaling described in the Mount Sinai study has been shown to correlate with high-grade tumors and poor patient prognosis. Based on previous studies, upregulation of Notch also confers drug resistance, particularly in the "triple-negative" cancer subtype that does not express estrogen receptor (ER), progesterone receptor (PR) or HER2.
The decision to focus on CBX8 resulted from an unconventional research strategy, according to Dr. Bernstein. Rather than selecting a particular molecular target or pathway because it had a proven track record in other types of cancer, the team decided to let genetic screening guide their decision-making. They screened a total of 60 epigenetic targets before homing in on CBX8.
"The novelty of the study comes from the fact that we did this in an unbiased manner," said Dr. Bernstein. "We didn't pick CBX8. It came to us in the screens because it has a dominant role in tumorigenesis."
Mount Sinai's work in the epigenetics of cancer is an important counter-balance to the lingering public perception that "genes are destiny." Despite years of scientific investigations into chemical factors that trigger or inhibit cell processes with no involvement of nucleic acid, DNA still rules when it comes to determining cancer. Today, Dr. Bernstein said, "doctors look at patients' genetics and their receptor status–HER2, estrogen and progesterone–and in some cases, they consider the tumor's gene expression profile. But we know these are not the only factors at work. Doctors concentrate on receptor status because the treatments we have today primarily target those pathways."
"Now, we are adding a new layer of analysis, and in time, I believe the patient's epigenetic status will be an important consideration," Dr. Bernstein said. "The nice thing about CBX8 as a potential factor to target–beside the fact that it regulates Notch signaling–is that it's independent of the breast cancer subtype. You could be positive or negative for HER2 or estrogen receptor. Either way, if you have high CBX8, that carries clinical significance. And it points to more of a general approach in targeting the epigenome, rather than receptor status or a specific gene expression profile."
While targeting epigenetic factors with drugs is still a relatively new therapeutic strategy, a number of such therapies are starting to move through clinical trials. "Now, at a time when chemical compounds are being developed to inhibit the CBX proteins, our work justifies focusing specifically on this one, CBX8, as a therapeutic target in the treatment of breast cancer," said Dr. Bernstein.
Contributors to this study include Chi-Yeh Chung, Zhen Sun, Gavriel Mullokandov, Almudena Bosch, Zulekha A. Qadeer, Esma Cihan, Zachary Rapp, Ramon Parsons, Julio A. Aguirre-Ghiso, Eduardo F. Farias, Brian D. Brown, Alexandre Gaspar-Maia, and Emily Bernstein.
This work was supported by the Office of Research Infrastructure of the NIH (award number S10OD018522), the Department of Defense Breast Cancer Research Program BC100975 and New York Stem Cell Foundation – Druckenmiller fellowship to A.G.M., NCI T32 T32CA078207-11 to Z.Q., Helmsley Trust Award to G.M., NIH Pathfinder Award (DP2DK083052-01) and Juvenile Diabetes Research Foundation (JDRF-17-2010-770) to B.D.B., R01 CA82783 and R01CA184016 to R.P., Samuel Waxman Cancer Research Foundation Tumor Dormancy Program to J.A.A.-G., E.F.F. and E.B., The JJR and Mary Kay Foundations to E.B.
Dr. Bernstein reports no conflicts of interest.
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