Abstract
Background Chemotherapy 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.
Methods The 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.
Results PEMF 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.
Conclusion The 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.
Competing Interest Statement
AFO is an inventor on patent WO 2019/17863 A1, System, and Method for Applying Pulsed Electromagnetic Fields as well as is a contributor to QuantumTx Pte. Ltd., which elaborates electromagnetic field devices for human use. All other authors declare no conflicts of interest.
List of abbreviations
- BCA
- bicinchoninic acid
- CAM
- chicken chorioallantoic membrane
- DCH2FDA
- 2’,7’-dichlorodihydrofluorescein diacetate
- DMEM
- Dulbecco’s Modified Eagle Medium
- DOX
- Doxorubicin
- dsiRNA
- dicer-substrate short interfering RNA
- EMT
- epithelial-mesenchymal transition
- IC50
- half maximal inhibitory concentration
- mT
- milliTesla
- NFAT
- nuclear factor of activated T-cells
- NOD-SCID
- nonobese diabetic/severe combined immunodeficiency
- NSG
- NOD-SCID gamma
- PDX
- patient-derived xenograft
- PEMF
- pulsed electromagnetic field
- PVDF
- polyvinylidene difluoride
- ROS
- reactive oxygen species
- RPMI
- Roswell Park Memorial Institute
- TBH
- tert-butylhydroperoxide
- TGFβ
- Transforming Growth Factor beta
- TRPC1
- Transient Receptor Potential Cation Channel C Member 1