High PARP1 expression is associated with proliferative tumor biology in breast cancer

Poly [ADP-ribose] polymerase (PARP) 1 enzyme is vital in DNA repair mechanisms. PARP1 inhibitors are in clinical use due to synthetic lethality in homologous-recombination repair-deficient tumors with germline BRCA1/2 mutations. Given that highly proliferative cancer requires excessive DNA replication and thus repair, we hypothesized that high PARP1 expression is associated with aggressive tumor biology in primary breast cancer regardless of subtype.

The gene expression profile of the primary breast cancer from 6351 patients from 3 independent cohorts (TCGA, METABRIC and SCAN-B) were analyzed by PARP1 expression. Transcriptomics data were analyzed in different subtypes of breast cancer separately. PARP1 high vs low expression groups was divided by the median in each cohort. PARP1 expression was also compared by response to neoadjuvant chemotherapy in 3 cohorts (GSE173839, GSE20566 and GSE20194).

PARP1 expression varied significantly across breast cancer subtypes, with lower expression in hormone-receptor positive (HR +) patients. High PARP1 expression was linked to increased mutation burden, particularly in HR + tumors. It also correlated with increased activity across multiple DNA repair pathways and increased cell proliferation, with enrichment in pathways related to cell cycle. Additionally, high-PARP1 tumors exhibited greater immune cell infiltration, particularly in HR + cases. In neoadjuvant chemotherapy studies, higher PARP1 expression levels were seen in patients with pathologic complete response (pCR) rates after preoperative chemotherapy, especially in HR + subtype.

Expression of PARP1 gene is associated with aggressive cancer biology, especially in the HR + subtype of breast cancer, and may serve as a biomarker for response to chemotherapy.