Enhanced immortalization, mutations and other biological drivers of breast invasive carcinoma in Black/African American patients.

Black/African-American (B/AA) breast cancer patients tend to have more aggressive tumor biology compared to White/Caucasians. In this study, a variety of breast tumor molecular expression profiles of patients derived from the two racial groupings were investigated. Breast invasive carcinoma sample data (RNASeq version 2, Reverse Phase Protein Array, mutation, and miRSeq data) from the Cancer Genome Atlas were examined. The results affirm that B/AA patients are more likely than Caucasian patients to harbor the aggressive or the poor prognosis-associated molecular subtypes of breast cancer. There is also a higher incidence of the triple-negative breast cancer (TNBC) among B/AA patients than the general population, a fact reflected in the mutation patterns of genes such as and . Furthermore, an immortalization signature gene set, is enriched in samples from B/AA patients. Among stage III patients, TERT, DRAP1, and PQBP1, all members of the immortalization gene signature set, are among master-regulators with increased activity in B/AA patients. Master-regulators driving differences in expression profiles between the two groups include immortalization markers, senescence markers, and immune response and redox gene products. Differences in expression, between B/AA and Caucasian patients, of , , , , , and other biomolecules appear to cooperate to enhance entry into the S-phase of the cell cycle in B/AA patients. Higher expression of , an oncomiR that facilitates entry into the cell cycle S-phase, is regulated by , which is expressed more in breast cancer samples from B/AA patients. Furthermore, the cell migration- and invasion-promoting miRNA, , has increased relative expression in B/AA patients. Knock down of the immortalization marker inhibited triple-negative breast cancer cell lines (MDA-MB-231 and MDA-MB-468) cell viability and decreased expression of TERT, MYC and WNT11. For those patients with available survival data, prognosis of stage II patients 50 years of age or younger at diagnosis, was distinctly poorer in B/AA patients. Also associated with this subset of B/AA patients are missense mutations in and expression loss. Relative to Caucasian non-responders to endocrine therapy, B/AA non-responders show suppressed expression of a signature gene set on which biological processes including , , , , and are over-represented. Thus, we identify molecular expression patterns suggesting diminished response to oxidative stress, changes in regulation of tumor suppressors/facilitators, and enhanced immortalization in B/AA patients are likely important in defining the more aggressive molecular tumor phenotype reported in B/AA patients.