Targeting African American and Ashkenazi Jewish Triple Negative Breast Cancers

Grant Winners

Deans

Abstract

Triple negative breast cancer (BC) is the most aggressive and least studied type of BC, and the most common BC subtype in African American (AA) and Ashkenazi Jewish women. Triple negative BC is defined as estrogen receptor, progesterone receptor, and Her2, negative.  At every stage, triple negative BC has significantly greater associated mortality than the other types of BC.  Recently, some investigators have suggested that triple negative BC has lower DNA repair capacity than other types of BC.  This conflicts with clinical data showing that DNA damaging chemotherapy drugs are less effective at controlling triple negative BC than other BC types.  We hypothesize that DNA (Nucleotide Excision) repair (NER) capacity is actually higher in triple negative BC, giving rise to treatment refractory tumors.  We further propose that reducing DNA repair gene expression via two epigenetic mechanisms will result in a targeted treatment strategy for triple negative BC. 

We will assess DNA repair capacity, specifically NER, in representative triple negative BC cell lines we have created, as well as in additional AA and Ashkenazi Jewish samples obtained from our clinical collaborator, Dr. Marshall.  We will assess the expression of the 20 canonical genes in the NER pathway to determine which are upregulated and therefore associated with the increase in functional repair.  Data from cell lines derived from AA and Caucasian women will be compared with those representing Ashkenazi Jewish women to determine whether the disease has similarly disregulated repair in all three of these populations. In future, we will determine the molecular mechanism of repair induction by suppressing expression of  NER genes with regulatory miRNAs.  Modulation of functional DNA repair in tumors that are triple negative, even for a short time, will render these tumor cells more vulnerable to genotoxic chemotherapy, and provide a desperately needed targeted treatment for triple negative disease.