1. ¹Division of Cancer Studies, School of Medicine, Oxford Road, Manchester M13 9PT, UK
2. ²School of Biological Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, UK

Correspondence: NG Anderson, University of Manchester, G186 Stopford Bldg, Oxford Road, Manchester M13 9PT, UK. E-mail: neil.anderson@man.ac.uk

Received 30 May 2002; Revised 18 November 2002; Accepted 19 November 2002.

Abstract

Overproduction of parathyroid hormone-related protein (PTHRP) occurs in a high proportion of primary breast cancers (PBC) and is strongly implicated in their metastatic spread to bone. Although the PTHRP-receptor (PTHRP-R) is often coexpressed with PTHRP in PBC, its role in regulating breast cancer cell proliferation and metastases to bone remains unclear. The aims of this study were to determine the expression of the PTHRP-R in breast cancer bone metastases (BM) and to investigate the effects of PTHRP-R overexpression on breast cancer cell proliferation. PTHRP-R expression occurred in 85% (11 out of 13) of BM compared with 58% (39 out of 67) of PBC. Median expression was higher (P<0.05) in BM compared with PBC. PTHRP increased cAMP accumulation and DNA synthesis in MCF-7 cells stably overexpressing the PTHRP-R (MCF-7^WTR) but not in MCF-7^VEC control cells. The increase in DNA synthesis was mimicked by the cAMP pathway activator forskolin. The receptor antagonist PTHRP_7–34 reduced DNA synthesis in MCF-7^WTR cells, but not MCF-7^VEC cells, indicating that receptor overexpression promotes autocrine PTHRP activity. MCF-7^WTR cells showed increased mitogenic responsiveness to fetal calf serum and reduced doubling times. PTHRP induced weak activation of ERK1 and ERK2 and potentiated their activation by serum growth factors. Collectively these results show that the PTHRP-R is frequently expressed in breast cancer BM and indicate that receptor overexpression drives proliferation via autocrine signals that are mediated via cAMP and ERK pathways.