Amplification of a calcium channel subunit CACNG4 increases breast cancer metastasis
Nisha Kanwar,
Katia Carmine-Simmen,
Ranju Nair,
Chunjie Wang,
Soode Moghadas-Jafari,
Heiko Blaser,
Danh Tran-Thanh,
Dongyu Wang,
Peiqi Wang,
Jenny Wang,
Adrian Pasculescu,
Alessandro Datti,
Tak Mak,
John D. Lewis,
Susan J. Done
Affiliations
Nisha Kanwar
The Campbell Family for Breast Cancer Research, Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada; Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A1, Canada
Katia Carmine-Simmen
Department of Oncology, University of Alberta, Edmonton, AB T6G 2E1, Canada
Ranju Nair
The Campbell Family for Breast Cancer Research, Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada
Chunjie Wang
Department of Pathology and Laboratory Medicine, Saskatoon City Hospital, Saskatoon, SK S7K 0M7, Canada
Soode Moghadas-Jafari
The Campbell Family for Breast Cancer Research, Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada
Heiko Blaser
The Campbell Family for Breast Cancer Research, Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada
Danh Tran-Thanh
Department of Pathology, Centre Hospitalier de l'Université de Montréal, Montréal, QC H2W 1T8, Canada
Dongyu Wang
Department of Medical Biophysics, Faculty of Medicine, University of Toronto, ON M5S 1A1, Canada
Peiqi Wang
The Campbell Family for Breast Cancer Research, Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada
Jenny Wang
Samuel Lunenfeld Research Institute, Mt. Sinai Hospital, Toronto, ON M5G 1X5, Canada
Adrian Pasculescu
Samuel Lunenfeld Research Institute, Mt. Sinai Hospital, Toronto, ON M5G 1X5, Canada
Alessandro Datti
Samuel Lunenfeld Research Institute, Mt. Sinai Hospital, Toronto, ON M5G 1X5, Canada; Department of Agricultural, Food, and Environmental Sciences, University of Perugia, Perugia, Italy
Tak Mak
The Campbell Family for Breast Cancer Research, Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada; Department of Medical Biophysics, Faculty of Medicine, University of Toronto, ON M5S 1A1, Canada
John D. Lewis
Department of Oncology, University of Alberta, Edmonton, AB T6G 2E1, Canada
Susan J. Done
The Campbell Family for Breast Cancer Research, Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada; Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A1, Canada; Department of Medical Biophysics, Faculty of Medicine, University of Toronto, ON M5S 1A1, Canada; Laboratory Medicine Program, Department of Pathology, University Health Network, Toronto General Hospital, 200 Elizabeth Street, 11th floor, Toronto, ON M5G 2C4, Canada; Corresponding author at: Laboratory Medicine Program, Department of Pathology, University Health Network, Toronto General Hospital, 200 Elizabeth Street, 11th floor, Toronto, ON M5G 2C4, Canada.
Background: Previously, we found that amplification of chromosome 17q24.1-24.2 is associated with lymph node metastasis, tumour size, and lymphovascular invasion in invasive ductal carcinoma. A gene within this amplicon, CACNG4, an L-type voltage-gated calcium channel gamma subunit, is elevated in breast cancers with poor prognosis. Calcium homeostasis is achieved by maintaining low intracellular calcium levels. Altering calcium influx/efflux mechanisms allows tumour cells to maintain homeostasis despite high serum calcium levels often associated with advanced cancer (hypercalcemia) and aberrant calcium signaling. Methods: In vitro 2-D and 3-D assays, and intracellular calcium influx assays were utilized to measure tumourigenic activity in response to altered CANCG4 levels and calcium channel blockers. A chick-CAM model and mouse model for metastasis confirmed these results in vivo. Findings: CACNG4 alters cell motility in vitro, induces malignant transformation in 3-dimensional culture, and increases lung-specific metastasis in vivo. CACNG4 functions by closing the channel pore, inhibiting calcium influx, and altering calcium signaling events involving key survival and metastatic pathway genes (AKT2, HDAC3, RASA1 and PKCζ). Interpretation: CACNG4 may promote homeostasis, thus increasing the survival and metastatic ability of tumour cells in breast cancer. Our findings suggest an underlying pathway for tumour growth and dissemination regulated by CACNG4 that is significant with respect to developing treatments that target these channels in tumours with aberrant calcium signaling. Funding: Canadian Breast Cancer Foundation, Ontario; Canadian Institutes of Health Research. Keywords: Breast cancer metastasis, Gamma subunits, L-type channels, Voltage-gated calcium channels (VGCCs)
