Aggressiveness and Metastatic Potential of Breast Cancer Cells Co-Cultured with Preadipocytes and Exposed to an Environmental Pollutant Dioxin: An in Vitro and in Vivo Zebrafish Study

Abstract

Background: Breast cancer (BC) is a major public health concern, and its prognosis is very poor once metastasis occurs. The tumor microenvironment and chemical pollution have been suggested recently to contribute, independently, to the development of metastatic cells. The BC microenvironment consists, in part, of adipocytes and preadipocytes in which persistent organic pollutants (POPs) can be stored. Objectives: We aimed to test the hypothesis that these two factors (2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD), an extensively studied, toxic POP and the microenvironment) may interact to increase tumor aggressiveness. Methods: We used a co-culture model using BC MCF-7 cells or MDA-MB-231 cells together with hMADS preadipocytes to investigate the contribution of the microenvironment and 2,3,7,8-tetrachlorodibenzo- p -dioxin TCDD on BC cells. Global differences were characterized using a high-throughput proteomic assay. Subsequently we measured the BC stem cell–like activity, analyzed the cell morphology, and used a zebrafish larvae model to study the metastatic potential of the BC cells. Results: We found that coexposure to TCDD and preadipocytes modified BC cell properties; moreover, it induced the expression of ALDH1A3, a cancer stem cell marker, and the appearance of giant cancer cells with cell-in-cell structures (CICs), which are associated with malignant metastatic progression, that we demonstrated in vivo . Discussion: The results of our study using BC cell lines co-cultured with preadipocytes and a POP and an in vivo zebrafish model of metastasis suggest that the interactions between BC cells and their microenvironment could affect their invasive or metastatic potential. https://doi.org/10.1289/EHP7102

Impact of mixtures of persistent organic pollutants on breast cancer aggressiveness

“…The results support that mixtures of dioxin-like pollutants may be associated with metastasis and tumor size in patients with a BMI > 22 kg/m 2 . These clinical results are coherent with in vitro studies (Koual et al, 2021). Despite several low-chlorinated PCB congeners being negatively associated with metastatic risk, interactions between POPs were not identified.…”

Environmental exposure and the role of AhR in the tumor microenvironment of breast cancer

“…IL-22 has also been described to mediate macrophage infiltration in the TME and the migration of breast cancer cells ( Kim et al, 2020 ). Results from MCF-7 cells co-cultured with preadipocytes and an in vivo zebrafish model showed that prototypical AhR ligand TCDD enhanced the invasive and metastatic potential of MCF-7 cells implicating the importance of AhR in the TME ( Koual et al, 2021 ).…”

Uncovering Evidence: Associations between Environmental Contaminants and Disparities in Women’s Health

“…Lifestyle habits may also influence disparities in breast cancer. For example, it has been reported that cigarette smoking (an activity that releases PCDDs) promotes the metastasis of breast cancer into the pulmonary system [77,78]. Despite these data and the known influence of inherent genetic differences, the potential role of gene-environment interactions in the development of cancer and/or the racial disparity in breast cancer type and mortality has not been well investigated.…”

“…The potential for gene-environment interactions is relevant to the discussion regarding EDC exposure and breast cancer, as PCDDs and some PCBs appear to promote breast cancer metastasis into the lymph node [78]. Reynolds et al collected adipose tissue from breast cancer patients of various races and measured the levels of environmental contaminants.…”