A key molecular player in recurrent breast cancer has been discovered by Perelman School of Medicine researchers.
The study, performed in the laboratory of Lewis A. Chodosh MD, PhD, chair of Cancer Biology and director of Cancer Genetics at the Abramson Family Cancer Research Institute, implicates the tumor suppressor protein Par-4 in recurrent breast cancer.
Par-4 is downregulated in recurrent tumors, and knocking the gene's expression down accelerates tumor recurrence in a mouse model of recurrent breast cancer. Conversely, overexpressing Par-4 delays the onset of tumor recurrence.
Data from human breast cancer patients confirm these findings. The authors analyzed patient tumors from the I-SPY 1 TRIAL, a clinical trial that measured tumor gene expression patterns and response to neoadjuvant chemotherapy.
They found that Par-4 expression is low in "residual disease" (that portion of a tumor that survives chemotherapy) compared to the primary tumor prior to treatment, and that women with low Par-4 levels in their primary tumors tend to respond less well to treatment and are more likely to experience a relapse.
The study was led by Chodosh senior postdoctoral fellow, James V. Alvarez, PhD. Alvarez and his colleagues teased apart the role of Par-4 using a mouse model of recurrent breast cancer.
The bottom line, Alvarez said, is that Par-4 downregulation is both a necessary and sufficient step for breast tumor recurrence.
That conclusion suggests that strategies that increase Par-4 expression in tumors could pay therapeutic dividends. In fact, turning Par-4 back on in recurrent tumor cells led to their rapid death. However, "drugging' Par-4 won't be easy", he says.
Par-4 is a tumor suppressor protein that functions through interactions with other proteins. Neither an enzyme nor a signaling receptor, it is not a traditionally "druggable" molecule. However, if researchers can identify the biochemical pathway that controls Par-4, or molecules that can modulate Par-4 activity directly, they may be able to increase the efficacy of neoadjuvant therapy of primary tumors as well as treat recurrent breast cancers more effectively, Alvarez said.
The team is now working on identifying pathways that regulate Par-4 levels.
The findings appear in this week's issue of Cancer Cell.