Endocrine disruptor chlorpyrifos promotes migration, invasion, and stemness phenotype in 3D cultures of breast cancer cells and induces a wide range of pathways involved in cancer progression

MARIANELA LASAGNA; CLARA VENTURA; SOLEDAD HIELPOS; MARIANA MARDIROSIAN; GABRIELA MARTIN; NOELIA MIRET; ANDREA RANDI; MARIEL NÚÑEZ; CLAUDIA COCCA

ENVIRONMENTAL RESEARCH

ACADEMIC PRESS INC ELSEVIER SCIENCE

Lugar: Amsterdam; Año: 2022 vol. 204

0013-9351

Organophosphorus chlorpyrifos (CPF) is currently considered an endocrine disruptor (ED), as it can imitatehormone actions both in vitro and in vivo. We recently reported that CPF induces migration and invasion in 2Dcultures and changes the expression of key molecular markers involved in epithelial mesenchymal transition inMCF-7 and MDA-MB-231 cell lines. In this study, we investigated whether CPF could behave as a predisposingfactor for tumors to become more metastatic and aggressive using 3D culture models. In MCF-7 cells, 0.05 μMCPF induced an increase in the number and size of mammospheres via estrogen receptor alpha (ERα) and c-SRC.Furthermore, 0.05 μM CPF increased the area of spheroids generated from MCF-7 cells, induced invasion usingboth Matrigel® and type 1 collagen matrices, and increased cell migration capacity via ERα in this 3D model. Inturn, 50 μM CPF increased cell migration capacity and invasion using type 1 collagen matrix. In monolayers, CPFincreased the phosphorylation and membrane translocation of c-SRC at both concentrations assayed. CPF at 0.05μM boosted p-AKT, p-GSK-3β and p-P38. While p-AKT rose in a ERα-dependent way, p-GSK-3β was dependent onERα- and c-SRC, and p-P38 was only dependent on c-SRC. On the other hand, the increase in p-AKT and p-P38induced by 50 μM CPF was dependent on the c-SRC pathway. We also observed that 0.05 μM CPF increased IGF-1R and IRS-1 expression and that 50 μM CPF induced IGF-1Rβ phosphorylation. In the MDA-MB-231 cell line,0.05 and 50 μM CPF increased p-c-SRC. Finally, p-AKT and p-GSK-3β were also induced by CPF at 0.05 and 50μM, and an increase in p-P38 was observed at 50 μM. Taken together, these data provide support for the notionthat CPF may represent a risk factor for breast cancer development and progression.