TRANSACTIVATION OF THE PTHRP GENE IN SQUAMOUS CARCINOMAS PREDICTS THEOCCURRENCE OF HYPERCALCEMIA IN ATHYMIC MICE

Humoral hypercalcemia of malignancy (HHM) is caused by the secretion o f parathyroid hormone-related protein (PTHrP) by tumor cells, and tumo rs of squamous histology are the ones most commonly complicated by HHM . To determine why some squamous tumors cause HHM and others do not, w e quantitated the levels of PTHrP mRNA expression and PTHrP secretion in a series of eight squamous tumor lines. As anticipated, we found th at the level of PTHrP mRNA expression in individual lines correlated w ith their PTHrP secretion rates. However, PTHrP mRNA levels varied wid ely in individual lines, and only those tumor lines with the highest L evels of PTHrP gene expression were able to cause hypercalcemia in ath ymic mice. We found that a specific segment of the PTHrP promoter coul d reproduce the relative pattern of PTHrP gene expression when cloned in front of a chloramphenicol acetyltransferase reporter gene and tran siently transfected into these squamous lines. Deletional analysis con firmed that specific sequences within the PTHrP gene promoter appeared to be invoiced in the transactivation of the gene in tumor lines expr essing high levels of PTHrP mRNA. These data suggest that the ability of a given squamous tumor to cause HHM is ultimately a function of its level of PTHrP gene expression, which in turn appears to be a functio n of the ability of specific transcription factors to transactivate PT HrP gene expression.