TNBC [ER-/PR-/HER2 wild-type] is frequently chemotherapy-resistant and carries a poor prognosis, particularly in Black/African American women. The molecular mechanisms of TNBC-initiation in Black/African- American and Latina/Hispanic women are poorly understood. It has been long suspected that disparities in nutrition and exposure to carcinogens may increase breast cancer-risk. Women-of-color experience discrimination in neighborhoods and housing that result in lack of access to healthy foods and increased exposure to heavy metals such as lead, arsenic, and cadmium. Genomic imprinting is an inherited form of epigenetic gene regulation that links disparities in nutrition and heavy metal exposure to lifelong risk for obesity, autism, heart disease, and cancer. We hypothesized that that abnormal imprinting might link disparities in nutrition and housing with aggressive TNBC biology. In preliminary data, we investigated KCNK9 (TASK3 protein), a pH-sensitive potassium channel protein that is overexpressed in a majority (91%) of TNBC that occur in Black/African-American women. When overexpressed, TASK3 increases mitochondrial membrane protein, apoptosis-resistance, and promotes aggressive TNBC biology. Here we aim to develop selective/high affinity TASK3 inhibitors. To do this we established an in silico homology model for the human TASK3 dimer. Four potential ?druggable? interaction sites were identified. In this pilot project we aim to test the hypothesis that TASK3 is a viable target for both treatment and prevention of TNBC in Black/African- American and Latina/Hispanic women.
Aim 1 will perform in vitro screening and structure-function optimization of lead TASK3 inhibitors (Perry, McCune).
Aim 2 will characterize the drug stability and pharmacokinetics of TASK inhibitors (Perry, McCune, Sistrunk).
We hypothesized that abnormal imprinting might link disparities in nutrition and housing with aggressive TNBC biology, in preliminary data we investigated KCNK9 (TASK3 protein), a pH-sensitive potassium channel protein that is overexpressed in a majority (91%) of TNBC that occur in Black/African-American women. When overexpressed, TASK3 increases mitochondrial membrane protein, apoptosis-resistance, and promotes aggressive TNBC biology. Here we aim to develop selective/high affinity TASK3 inhibitors for treatment and prevention of TNBC in Black/African-American and Latinas/Hispanic women.
