Targeting Drivers of Aggressive Triple-Negative Breast Cancer in African Americans
[Technical Report, Final Report]
WASHINGTON UNIV ST LOUIS MO
Pagination or Media Count:
Triple-negative breast cancer TNBC is an overly aggressive breast cancer subtype that disproportionately affects African American women. TNBC is characterized by a lack of expression of the estrogen and progesterone receptors as well as the absence of HER2 amplification. TP53 mutations are the only genetic correlate with poor clinical prognosis in this subtype. We found that p53 mutations in TNBC often coincided with deletionsilencing of the CDKN2A locus that encodes both the ARF and INK4A tumor suppressors. This genetic context was primarily present in African American women with TNBC. Concurrent loss of both p53 and CDKN2A function resulted in massive gains in proliferation and transformation of mouse and human mammary epithelial cells both in vitro and in vivo. These phenotypic tumor gains were the direct result of altered JAK1 and CDK4 activity. JAK1 and CDK4 cooperate to stimulate breast tumor cell proliferation. In our final report, we provide direct evidence that this pathway is altered in TNBC and that targeting this pathway might be a fundamentally plausible avenue for future TNBC treatments.
- Medicine and Medical Research