Modulated TRPC1 expression predicts sensitivity of breast cancer to doxorubicin and magnetic field therapy: segue towards a precision medicine approach.

Abstract

BackgroundChemotherapy is the mainstream treatment modality for invasive breast cancer. Nonetheless, chemotherapy-associated adverse events can result in a patient terminating treatment. We show that transient receptor potential channel 1 (TRPC1) expression level predicts breast cancer sensitivity to doxorubicin (DOX) and pulsed electromagnetic field (PEMF) therapies. MethodsThe effects of PEMFs were examined with respect to: 1) the growth of MCF-7 cells in vitro; 2) MCF-7 tumors implanted into a chicken chorioallantoic membrane (CAM) model and; 3) patient-derived and MCF-7 breast cancer xenografts in mice. Potential synergisms between DOX and PEMF therapies were examined in these model systems and under conditions of TRPC1 overexpression or silencing in vitro. ResultsPEMF exposure impaired the survival of MCF-7 cells, but not that of nonmalignant MCF10A breast cells. The effects of PEMF- and DOX-therapies synergized in vitro at compromising MCF-7 cell growth. Synergism could be corroborated in vivo with patient-derived xenograft mouse models, wherein PEMF exposure alone or in combination with DOX reduced tumor size. Stable overexpression of TRPC1 enhanced the vulnerability of MCF-7 cells to both DOX and PEMF exposure and promoted proliferation, whereas chronic DOX exposure reduced TRPC1 expression, induced chemoresistance, precluded response to PEMF exposure and mitigated proliferation. Markers of metastasis including SLUG, SNAIL, VIMENTIN, and E-CADHERIN as well as invasiveness were also positively correlated with TRPC1 channel expression. ConclusionThe presented data supports a potential role of PEMF-therapy as an effective companion therapy to DOX-based chemotherapy for the treatment of breast cancers characterized by elevated TRPC1 expression levels.