The calcium-sensing receptor (CaSR) plays a pivotal role in systemic calcium 
metabolism by regulating parathyroid hormone secretion and urinary calcium 
excretion. The CaSR is ubiquitously expressed, implying a wide range of 
functions regulated by this receptor. Abnormal CaSR function affects the 
development of both calciotropic disorders such as hyperparathyroidism, and 
non-calciotropic disorders such as cardiovascular disease and cancer, which are 
the leading causes of mortality worldwide. The CaSR is able to bind a plethora 
of ligands; it interacts with multiple G protein subtypes, and regulates highly 
divergent downstream signalling pathways, depending on the cellular context. The 
CaSR is a key regulator for such diverse processes as hormone secretion, gene 
expression, inflammation, proliferation, differentiation, and apoptosis. Due to 
this pleiotropy, the CaSR is able to regulate cell fate and is implicated in the 
development of many types of benign or malignant tumours of the breast, 
prostate, parathyroid, and colon. In cancer, the CaSR appears to have 
paradoxical roles, and depending on the tissue involved, it is able to prevent 
or promote tumour growth. In tissues like the parathyroid or colon, the CaSR 
inhibits proliferation and induces terminal differentiation of the cells. 
Therefore, loss of the receptor, as seen in colorectal or parathyroid tumours, 
confers malignant potential, suggestive of a tumour suppressor role. In 
contrast, in prostate and breast tumours the expression of the CaSR is increased 
and it seems that it favours metastasis to the bone, acting as an oncogene. 
Deciphering the molecular mechanism driving the CaSR in the different tissues 
could lead to development of new allosteric drug compounds that selectively 
target the CaSR and have therapeutic potential for cancer. This article is part 
of a Special Issue entitled: Calcium and Cell Fate. Guest Editors: Jacques 
Haiech, Claus Heizmann, Joachim Krebs, Thierry Capiod and Olivier Mignen.