Northeastern University

Leveraging the synergistic anti-proliferative effect of SHMT2 and CDK4 in triple negative breast cancer

Brian Shim with Dr. William Hahn (DFCI)

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that is clinically characterized by a lack of expression of the most common identifying receptors of breast cancer: ER, PR, and HER2. TNBC composes 10-20% of all breast cancer patients, and has the worst outcomes of all breast cancer subtypes. While numerous breast cancer gene signatures and biomarkers have been studied as therapeutic targets and predictors of survival, the poorly understood molecular biology behind TNBC has made it particularly challenging to target. Human SHMT2–an essential enzyme involved in the folate cycle and highly implicated in de novo nucleotide synthesis–has been presented in previous studies as a valid predictive and prognostic biomarker for TNBC subgroups. Moreover, SHMT2 has found in multiple patient datasets to be highly co-expressed with CDK4, a cell cycle regulator. This is interesting since CDK4/6 inhibitors such as palbociclib are now first-line for upfront clinical treatment in luminal and HER2+ breast cancers. Since both cell cycle and nucleotide synthesis dysregulation are implicated in malignant cancer cells, I hypothesize that simultaneous exogenous manipulation of SHMT2 and CDK4 may have a synergistic anti-proliferative effect that increases the therapeutic effect of CDK4/6 inhibitors in TNBC. Over the course of my co-op, I plan to use both genetic and pharmacological approaches to test the relationship between SHMT2 and CDK4 in vitro in an attempt to uncover a potential novel therapeutic avenue for TNBC patients.