DNA damage response inhibition is an early event in cadmium-induced breast carcinogenesis

Abstract

Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer with few treatment options that disproportionately affects individuals with Breast Cancer 1 (BRCA1) gene mutations and young, non-Hispanic Black women. However, BRCA1 mutation frequencies are similar among women from all races/ethnicities, with the exception of Ashkenazi Jewish women, suggesting that gene-environment interactions contribute to TNBC disparities. Environmental cadmium (Cd) exposure is positively associated with breast cancer and Cd accumulates in human breast tumors compared to normal adjacent tissue. Previous work determined that Cd exposure promotes MCF10A cell malignant transformation after 40 weeks. Here, we report that chronic Cd exposure dysregulates essential metal homeostasis and promotes significant accumulation of DNA double-strand breaks (DSBs). Moreover, phosphorylation of Breast Cancer gene 1 (BRCA1) and Tumor Protein P53 (TP53) at critical sites (pSer1524 and pSer392, respectively) required for DNA damage response (DDR) signaling were significantly reduced by chronic Cd exposure in pre-malignant MCF10A cells. We also demonstrate significantly lower cyclin dependent kinase inhibitor 1A (CDKN1A) expression and increased RB1 phosphorylation (pSer807/811), providing evidence for reduced BRCA1 and/or TP53 function in cells chronically exposed to Cd. Our results suggest that chronic Cd exposure inhibits DDR signaling both indirectly by depletion of essential metals and by inhibition of DDR zinc finger protein activation, providing novel mechanisms for environmentally-induced TNBC. As a result, our study provides a molecular mechanism that may contribute to TNBC disparities.