Targeting Drivers of Aggressive Triple-Negative Breast Cancer in African Americans
Technical Report,01 Mar 2019,28 Feb 2020
Washington University St. Louis United States
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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 amplificationmutation. 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 deletionsilencing 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.
- Medicine and Medical Research