Environmental chemicals, breast cancer progression and drug resistance

Abstract

Breast cancer (BC) is one of the most common causes of cancer in the world and the second leading cause of cancer deaths among women. Mortality is associated mainly with the development of metastases. Identification of the mechanisms involved in metastasis formation is, therefore, a major public health issue. Among the proposed risk factors, chemical environment and pollution are increasingly suggested to have an effect on the signaling pathways involved in metastatic tumor cells emergence and progression. The purpose of this article is to summarize current knowledge about the role of environmental chemicals in breast cancer progression, metastasis formation and resistance to chemotherapy. Through a scoping review, we highlight the effects of a wide variety of environmental toxicants, including persistent organic pollutants and endocrine disruptors, on invasion mechanisms and metastatic processes in BC. We identified the epithelial-to-mesenchymal transition and cancer-stemness (the stem cell-like phenotype in tumors), two mechanisms suspected of playing key roles in the development of metastases and linked to chemoresistance, as potential targets of contaminants. We discuss then the recently described pro-migratory and pro-invasive Ah receptor signaling pathway and conclude that his role in BC progression is still controversial. In conclusion, although several pertinent pathways for the effects of xenobiotics have been identified, the mechanisms of actions for multiple other molecules remain to be established. The integral role of xenobiotics in the exposome in BC needs to be further explored through additional relevant epidemiological studies that can be extended to molecular mechanisms.

Keywords: Breast cancer; Endocrine disrupting chemicals; Environmental exposure; Environmental pollutants; aryl hydrocarbon receptor; cancer stem cells; drug resistance; Organochlorine pesticides; Perfluoroalkyl acid; Polychlorinated biphenyls.

Fig. 1

Flow diagram of the study selection

Fig. 2

Epithelial-to-mesenchymal transition and appearance of cancer stem cells are two mechanisms which are suspected to lead to the occurrence of metastasis. EMT is associated to the phenotypical acquisition of cellular properties which leads to the migration and invasion of primary tumor cells while cancer stem cells conserve cellular properties of stem cells (important for maintenance and renewal of the breast cellular epithelium) which maintain cancer proliferation, metastatic dissemination and resistance to anticancer treatment. The figure also synthesized the processes which are targeted by environmental pollutants (orange squares). This figure was drawn using the website « Smart Servier Medical Art » (https://smart.servier.com/)