The protein CBX8 uses a previously unknown mechanism to promote the origin of breast tumors, or tumorigenesis, in the most lethal forms of breast cancer, according to new research. This finding underscores the need for cancer researchers to pay more attention to epigenetic factors, the chemical and biological processes that control gene expression but do not change the underlying DNA sequence of the cells that are running amok.1
“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,” explained Emily Bernstein, PhD, associate professor of oncological sciences and dermatology at the Icahn School of Medicine at Mount Sinai, New York, New York. “We also know that CBX8 is overexpressed in primary breast tumors, and that high CBX8 expression in patients correlates with poor outcome.”
The researchers found that CBX8 has an expression pattern in breast cancer cells that is like stem cells. In particular, it is involved in Notch signaling, which is a cellular pathway that is important for both mammary development and tumorigenesis. Dysregulated CBX8 results in 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 study. “Our genomic analysis revealed, both in mouse and human breast cancer cell lines, that CBX8 promotes the Notch signaling pathway.”
Bernstein explained that their decision to focus on CBX8 came from an unconventional research strategy. 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 Bernstein. “We didn’t pick CBX8. It came to us in the screens because it has a dominant role in tumorigenesis.”
This focus on epigenetics is an important counterbalance to the lingering public perception that “genes are destiny.” Today, doctors focus on the genetics of a patient and their receptor status, meaning HER2, estrogen, and progesterone, because currently available treatments 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,” 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.”
1. Chung CY, Sun Z, Mullokandov G, et al. CBX8 acts non-canonically with Wdr5 to promote mammary tumorigenesis. Cell Reports. 2016 Jun 23. doi:10.1016/j.celrep.2016.06.002. [Epub ahead of print]