Cadmium stimulates metastasis-associated phenotype in triple-negative breast cancer cells through integrin and β-catenin signaling

Abstract

Cadmium (Cd) is a carcinogenic heavy metal which is implicated in breast cancer development. While the mechanisms of Cd-induced breast cancer initiation and promotion have been studied, the molecular processes involved in breast cancer progression remain to be investigated. The purpose of the present study was to evaluate the influence of Cd on metastasis-associated phenotypes, such as cell adhesion, migration, and invasion in triple-negative breast cancer cells. Treatment of MDA-MB-231 cells with 1 μM Cd increased cell spreading and cell migration. This was associated with the activation of integrin β1, FAK, Src, and Rac1. Treatment with Cd also inhibited GSK3β activity and induced T-cell factor/lymphoid enhancer factor (TCF/LEF) transcription, indicating the involvement of β-catenin signaling. Furthermore, treatment with 3 μM Cd for 4 weeks increased the expression of β-catenin and enhanced TCF/LEF-mediated transcription. Furthermore, enhanced expressions of integrins α5 and β1, paxillin, and vimentin indicated that prolonged Cd treatment reorganized the cytoskeleton, which aided malignancy, as evidenced by enhanced matrix metalloprotease 2/9 (MMP2/9) secretion and cell invasion. Prolonged Cd treatment also caused an increase in cell growth. Together, these results indicate that Cd alters key signaling processes involved in the regulation of cytoskeleton to enhance cancer cell migration, invasion, adhesion, and proliferation.

Cadmium Exposure Inhibits Branching Morphogenesis and Causes Alterations Consistent With HIF-1α Inhibition in Human Primary Breast Organoids

“…The in vivo data of cadmium exposure during windows of susceptibility show that life stage of exposure is important, where in utero exposures to cadmium display an estrogenic effect leading to an increase in terminal end bud structures (Alonso-Gonzalez et al, 2007;Johnson et al, 2003), while exposures in puberty or adulthood lead to stunted mammary gland development (Davis et al, 2013;Ohrvik et al, 2006). A more limited number of in vitro studies of the effects of cadmium in immortalized breast cell lines highlight that cadmium exposure can lead to the acquisition of an invasive phenotype (Benbrahim-Tallaa et al, 2009;Wei and Shaikh 2017), consistent with dysregulation of the important developmental pathway the epithelial-mesenchymal transition (EMT). Despite a growing body of experimental and epidemiological evidence linking cadmium to altered mammary gland development and potentially breast cancer, very little is known about the effects of cadmium exposure on primary nontransformed and nonimmortalized human breast stem cells.…”

Cadmium exposure inhibits branching morphogenesis and causes alterations consistent with HIF-1α inhibition in human primary breast organoids

“…A forty-week treatment of the immortalized, but non-tumorigenic, breast cell line MCF10A with 0.25µM cadmium lead to the acquisition of an invasive, aggressive phenotype consistent with basal breast cancers through a mechanism independent of ER-a (Benbrahim-Tallaa et al 2009). Recently, treatment of MDAMB231 cells, an already aggressive and invasive triple negative breast cancer cell line, with 1uM or 3uM cadmium lead to a more invasive and metastatic phenotype (Wei and Shaikh 2017). While the results of these studies lead us to initially hypothesize that we would observe a similar EMT-like phenotype in cadmium treated primary breast stem cells, we instead observed the opposite.…”

“…The in vivo data of cadmium exposure during windows of susceptibility show that life stage of exposure is important, where in utero exposures to cadmium display an estrogenic effect leading to an increase in terminal end bud structures (Alonso-Gonzalez et al 2007;Johnson et al 2003), while exposures in puberty or adulthood lead to stunted mammary gland development Ohrvik et al 2006). A more limited number of in vitro studies of the effects of cadmium in immortalized breast cell lines highlight that cadmium exposure can lead to the acquisition of an invasive phenotype (Benbrahim-Tallaa et al 2009;Wei and Shaikh 2017), consistent with dysregulation of the important developmental pathway the epithelial-mesenchymal transition (EMT). Despite a growing body of experimental and epidemiological evidence linking cadmium to altered mammary gland development and potentially breast cancer, very little is known about the effects of cadmium exposure on primary non-transformed and non-immortalized human breast stem cells.…”

Chronic exposure to cadmium induces a malignant transformation of benign prostate epithelial cells

“…Recent studies have demonstrated that Shh activation plays a central role in EMT regulation, involving the loss of cell-cell adhesion, changes in cell morphology, and the propensity to migrate and invade CaP 43,44 . Wei and Shaikh 45 reported that prolonged Cd treatment in triplenegative breast cancer cells stimulates cell proliferation, adhesion, cytoskeleton reorganization, as well as migration and invasion. Here, we observed that both ZIC + cells and chronic exposure to Cd-induced expression of mesenchymal marker, β-catenin.…”