Cancers have been considered as one of the most severe health problems in the world. Efforts to elucidate the cancer progression reveal the importance of bone metastasis for tumor malignancy, one of the leading causes for high mortality rate. Multiple cancers develop bone metastasis, from which breast cancers exhibit the highest rate and have been well-recognized. Numerous cells and environmental factors have been believed to synergistically facilitate bone metastasis in breast cancers, from which breast cancer cells, osteoclasts, osteoblasts, and their produced cytokines have been well-recognized to form a vicious cycle that aggravates tumor malignancy. Except the cytokines or chemokines, calcium ions are another element largely released from bones during bone metastasis that leads to hypercalcemia, however, have not been well-characterized yet in modulation of bone metastasis. Calcium ions act as a type of unique second messenger that exhibits omnipotent functions in numerous cells, including tumor cells, osteoclasts, and osteoblasts. Calcium ions cannot be produced in the cells and are dynamically fluxed among extracellular calcium pools, intracellular calcium storages and cytosolic calcium signals, namely calcium homeostasis, raising a possibility that calcium ions released from bone during bone metastasis would further enhance bone metastasis and aggravate tumor progression via the vicious cycle due to abnormal calcium homeostasis in breast cancer cells, osteoclasts and osteoblasts. TRPs, VGCCs, SOCE, and P2Xs are four major calcium channels/routes mediating extracellular calcium entry and affect calcium homeostasis. Here we will summarize the overall functions of these four calcium channels in breast cancer cells, osteoclasts and osteoblasts, providing evidence of calcium homeostasis as a vicious cycle in modulation of bone metastasis in breast cancers.

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Clustered regularly interspaced short palindromic repeats (CRISPR)/ CRISPR-associated protein-9 nuclease (Cas9) technology is widely used as a tool for gene editing in rat genome site-specific engineering. Multidrug resistance 1 [MDR1 (also known as P-glycoprotein)] is a key efflux transporter that plays an important role not only in the transport of endogenous and exogenous substances, but also in tumor MDR. In this report, a novel MDR1 (Mdr1a/b) doubleknockout (KO) rat model was generated by the CRISPR/Cas9 system without any off-target effect detected. Western blot results showed that MDR1 was completely absent in the liver, small intestine, brain, and kidney of KO rats. Further pharmacokinetic studies of digoxin, a typical substrate of MDR1, confirmed the deficiency of MDR1 in vivo. To determine the possible compensatory mechanism of Mdr1a/b (2/2) rats, the mRNA levels of the CYP3A subfamily and transporter-related genes were compared in the brain, liver, kidney, and small intestine of KO and wild-type rats. In general, a new Mdr1a/b (2/2) rat model has been successfully generated and characterized. This rat model is a useful tool for studying the function of MDR1 in drug absorption, tumor MDR, and drug target validation.