Abstract A52: Targeted expression profiling identifies mechanisms of potential breast carcinogens

Abstract

Abstract Over 200 chemicals have been associated with altered mammary gland development and cancer in rodent studies, yet the molecular mechanisms by which this diverse set of chemicals affect the breast remain poorly understood. We examined gene expression profiles of eight known and suspected mammary toxicants using the TempO-Seq platform and a targeted gene expression panel, Breast Carcinogen Screen (BCScreen). The BCScreen panel has 500 genes with at least 30 genes strongly associated with each of the 14 biologic processes relevant to breast cancer and mammary gland development. We compared gene expression profiles in MCF-7 cells treated for 24hrs with four concentrations (1 nM to 10 uM) of the following chemicals: three estrogenic chemicals (genistein, bisphenol A, butyl benzyl phthalate); the selective estrogen receptor modulator, tamoxifen (TAM); 1,4 benzoquinone (BQ), a genotoxic metabolite of the rodent mammary carcinogen benzene; perfluorooctanoic acid (PFOA), a persistent pollutant that alters mammary gland development; and two closely related perfluorinated chemicals that have not been evaluated for mammary toxicity/effects (PFHXA, PFNA). We identified expression patterns activated by mammary toxicants with known ER agonist activity (genistein, BPA, BBP). Some of these genes were suppressed by PFOA and BQ and TAM, mammary toxicants with antagonist or no known direct ER activity. The known weak estrogens genistein, BPA, and BBP had similar gene expression profiles and were enriched for genes associated with cell cycle and DNA repair, particularly at higher doses. Notably, PFOA, Tam, and BQ had greater gene expression changes at lowest (1nM) vs. higher doses and were enriched for genes associated with cell cycle. For context, serum PFOA levels in the general US population are generally five to ten times higher than the 1 nM dose where we observed these changes (i.e., > 0.4 micrograms/L). PFOA profiles were enriched for several transcription factors including E2F1 and E2F4, which regulate cell cycle genes and important processes in mammary development and tumor progression. Utilizing the BCScreen gene panel, we have identified mechanistic targets relevant to breast cancer that are perturbed by mammary toxicants. Citation Format: Vanessa Y. De La Rosa, Erik Lehnert, Marko Milanovic, Chris Vulpe, Ruthann A. Rudel. Targeted expression profiling identifies mechanisms of potential breast carcinogens [abstract]. In: Proceedings of the AACR Special Conference on Environmental Carcinogenesis: Potential Pathway to Cancer Prevention; 2019 Jun 22-24; Charlotte, NC. Philadelphia (PA): AACR; Can Prev Res 2020;13(7 Suppl): Abstract nr A52.