Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer with high mortality that accounts for 15-20% of all breast cancer diagnoses. Patients experience high rates of relapse and metastasis. Molecular profiling shows that TNBC tumors can be classified into subtypes that differ in expression of epithelial and mesenchymal markers as well as in response to chemotherapy. TNBC cells enriched in mesenchymal markers are radiation and chemotherapy resistant, and may contribute to therapeutic resistance and tumor relapse. We previously discovered that silver nanoparticles (AgNPs) are cytotoxic to TNBCs at doses that have no effect on non-cancerous cells. Our current studies shown that TNBCs expressing mesenchymal markers (ZEB1, VIM, FN1) are significantly more sensitive to AgNPs than TNBCs that express epithelial markers (CDH1, ESRP1). Furthermore, lung, prostate, colorectal, and ovarian cancers that express mesenchymal markers are more sensitive to AgNPs than cancers of the same origin that express epithelial markers. This shared vulnerability of mesenchymal cancers to AgNPs indicates that there is an underlying biology that is responsible for this. We performed mechanistic studies to determine the cause of these differences. Our results show that AgNPs induce protein aggregation, endoplasmic reticulum stress, and lipid peroxidation in TNBCs expressing a mesenchymal phenotype, but not in epithelial TNBCs. We further identify elevated synthesis of extracellular matrix (ECM) proteins including fibronectin and collagen, as well as high expression of long-chain-fatty-acid CoA ligase 4 (ACSL4), as being distinguishing features of AgNP sensitive cancers. The burden of synthesis of ECM proteins increases sensitivity of cells to ER stress, and ACSL4 is essential for incorporating oxidizable lipids into cell membranes. By detailing these mechanisms of action and identifying genetic signatures associated with sensitivity to AgNPs, our results highlight shared vulnerabilities of mesenchymal cancer cell populations, which may be exploited by AgNPs or other therapies.

Identification of molecular signatures predictive of sensitivity of breast cancer cells to silver nanoparticles

ACS Fall 2020 Virtual Meeting

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.