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 Oncology, University of Alberta, Edmonton, AB T6G 2E1, Canada.
EBioMedicine. 2020 Feb;52:102646. doi: 10.1016/j.ebiom.2020.102646. Epub 2020 Feb 12.
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.
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.
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).
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.
Canadian Breast Cancer Foundation, Ontario; Canadian Institutes of Health Research.
此前，我们发现 17q24.1-24.2 染色体扩增与浸润性导管癌的淋巴结转移、肿瘤大小和血管淋巴管浸润有关。该扩增子内的一个基因 CACNG4 是 L 型电压门控钙通道 γ 亚基，在预后不良的乳腺癌中升高。钙稳态是通过维持细胞内低钙水平来实现的。改变钙内流/外流机制可以使肿瘤细胞在高血清钙水平（常与晚期癌症相关）和异常钙信号下维持稳态，高血清钙水平通常与晚期癌症（高钙血症）和异常钙信号相关。
利用体外 2-D 和 3-D 测定法和细胞内钙内流测定法，测量 CACNG4 水平和钙通道阻滞剂改变时的肿瘤发生活性。鸡胚绒毛尿囊膜模型和转移的小鼠模型在体内证实了这些结果。
CACNG4 在体外改变细胞迁移性，在 3 维培养中诱导恶性转化，并增加体内肺特异性转移。CACNG4 通过关闭通道孔、抑制钙内流以及改变涉及关键存活和转移途径基因（AKT2、HDAC3、RASA1 和 PKCζ）的钙信号事件起作用。
CACNG4 可能促进肿瘤细胞的稳态，从而增加乳腺癌中肿瘤细胞的存活和转移能力。我们的研究结果表明，CACNG4 调节肿瘤生长和扩散的潜在途径与开发针对钙信号异常肿瘤中这些通道的治疗方法具有重要意义。
加拿大乳腺癌基金会、安大略省；加拿大卫生研究院。
