Blocking SIG1R Along with Low Cadmium Exposure Display Anti-cancer Qualities in Both MCF7 and MDA-MB-231 Cells

Sigma-1 receptor (SIG1R) is a chaperone that modulates inositol 1,4,5-trisphosphate receptor type1 (IP₃R1) calcium (Ca²⁺) channels on the endoplasmic reticulum. Therefore, SIG1R functions as an indirect regulator of Ca²⁺ and acts as an apoptosis modulator. Increased expression of SIG1R is associated with poor prognosis in breast cancers (BC), and SIG1R antagonists like BD1047 induce apoptosis. As a heavy metal, cadmium (Cd²⁺) is competitive with Ca²⁺ due to its physicochemical similarities and may trigger apoptosis at low concentrations. Our study investigated the SIG1R protein expression in 74 BC patients and found a significant increase in SIG1R expression in the triple-negative BC subtype. We also examined the apoptotic and anti-cancer effects of BD1047 in combination with CdCl₂ in MCF7 and MDA-MB-213 cells. Cells were treated with CdCl₂ at doses of 1 μM, 25 μM, and 50 μM, along with BD1047. Higher doses of CdCl₂ were cytotoxic on both cancer cells and significantly increased DNA breaks. However, low-dose CdCl₂ with BD1047 increased cell death and the apoptotic index in BC cells, although it did not exhibit cytotoxic effects on HUVEC cells. Co-administration of low-dose CdCl₂ with BD1047 also reduced the migration and colony-forming ability of BC cells. Moreover, the expression of SIG1R protein in these groups decreased significantly compared to groups treated with BD1047 or low-dose CdCl₂ alone. In conclusion, low-dose CdCl₂ is thought to increase the apoptotic ability of BD1047 in BC cells by reducing SIG1R expression.