Previous reports have shown the production of parathyroid hormone-related protein (PTHrP) by breast cancer cells in vivo and in vitro. We have investigated the expression of the PTH/PTHrP receptor by the human breast cancer cell lines MCF-7, ZR-75-1, T-47-D, SK-BR-3, Hs578T and MDA-MB231. Using reverse transcription-polymerase chain reaction (RT-PCR) and Southern blot analysis, we detected transcripts for the receptor in MCF-7, SK-BR-3 and MDA-MB231 cells. There was no evidence of receptor mRNA in ZR-75-1 and Hs578T cells. Furthermore, Northern blot analysis of mRNA from MCF-7 cells showed two transcripts of 1.5 and 2.4 kb which coded for the PTH/PTHrP receptor. Expression of PTH/PTHrP receptor mRNA by the breast cancer cell lines was also correlated with the detection of PTHrP transcripts. RT-PCR demonstrated PTHrP mRNA in MCF-7, ZR-75-1, T-47-D and Hs578T cells, but not in SK-BR-3 and MDA-MB231 cells. The detection of receptor transcripts was complemented by [3H]thymidine and bromodeoxyuridine incorporation studies, in which mitogenic responses to PTH and PTHrP were observed in MCF-7 cells but not in Hs578T cells. In response to both PTH(1-34) and PTHrP(1-34), quiescent MCF-7 cells proliferated in a similar dose-dependent manner (1.6-100 ng ml-1). No mitogenic effects of these peptides were observed with Hs578T cells. In addition, levels of intracellular cAMP were measured in MCF-7 and Hs578T cells in response to PTHrP(1-34). In MCF-7 cells there was a significant rise in cAMP with 100 ng ml-1 PTHrP(1-34). The expression of PTH/PTHrP receptor by breast cancer cells suggests that PTHrP may be a paracrine/autocrine regulator of breast carcinoma.