Targeting Drivers of Aggressive Triple-Negative Breast Cancer in African Americans
Abstract
Triple-negative breast cancer (TNBC) is an overly aggressive breast cancer subtype that disproportionately affects African American women. Triple-negative breast cancer is characterized by a lack of expression of the estrogen and progesterone receptors as well as the absence of HER2 amplification/mutation. TP53 mutations are the only genetic correlate with poor clinical prognosis in this subtype. In our preliminary studies, we found that p53 mutations in TNBC often coincided with deletion/silencing of the CDKN2A locus that encodes both the ARF and INK4A tumor suppressors. Surprisingly, 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 (through loss of p53 and ARF) and CDK4 (through INK4A loss) activity. In this genetic context, JAK1 and CDK4 cooperate to stimulate breast tumor cell proliferation. For this reason, identifying these key growth-driving kinases is paramount to discovering novel combinatorial therapies for TNBC. In our year 2 report, we show that the JAK1 pathway is elevated in human TNBC that also have loss of ARF and p53 function. Moreover, we have determined that TNBC cell lines are uniquely sensitive to combined JAK1 and CDK4 inhibition in vitro.
Document Details
- Document Type
- Technical Report
- Publication Date
- Mar 01, 2020
- Accession Number
- AD1104133
Entities
People
- Jason D Weber
Organizations
- Washington University in St. Louis