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Parathyroid Hormone‐Related Peptide Stimulates Proliferation of Highly Tumorigenic Human SV40‐Immortalized Breast Epithelial Cells
Author(s) -
Cataisson Christophe,
Lieberherr Michele,
Cros Magali,
Gauville Christiane,
Graulet AnneMarie,
Cotton Joel,
Calvo Fabien,
de Vernejoul MarieChristine,
Foley John,
Bouizar Zhor
Publication year - 2000
Publication title -
journal of bone and mineral research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.882
H-Index - 241
eISSN - 1523-4681
pISSN - 0884-0431
DOI - 10.1359/jbmr.2000.15.11.2129
Subject(s) - parathyroid hormone related protein , autocrine signalling , endocrinology , medicine , cell culture , paracrine signalling , cell growth , signal transduction , receptor , cancer research , biology , chemistry , parathyroid hormone , microbiology and biotechnology , calcium , genetics
Parathyroid hormone‐related protein (PTHrP) is the main mediator of humoral hypercalcemia of malignancy (HHM) and it is produced by many tumors, including breast cancers. Breast epithelial cells as well as breast cancer tumors and cell lines have been reported as expressing PTHrP and the PTH/PTHrP receptor, suggesting that PTHrP may act as an autocrine factor influencing proliferation or differentiation of these cell types. We investigated PTHrP gene expression, PTH/PTHrP receptor signaling, and PTHrP‐induced mitogenesis in three immortalized human mammary epithelial cell lines that exhibit differential tumorigenicity. The most tumorigenic cells expressed the highest levels of PTHrP messenger RNA (mRNA) and protein. We used reverse‐transcription polymerase chain reaction (RT‐PCR) and immunoblotting to detect the PTH/PTHrP receptor transcripts and proteins in all of the three cell lines. Treatment with human PTHrP(1‐34) [hPTHrP(1‐34)] and hPTH(1‐34) increased intracellular cyclic adenosine monophosphate (cAMP) but not free Ca 2+ in the nontumorigenic line. These agonists increased both cAMP and free Ca 2+ levels in the moderately tumorigenic line, but only increased free Ca 2+ in the highly tumorigenic line. Application of the PTH/PTHrP receptor antagonist [Asn 10 ,Leu 11 ,D Trp 12 ]PTHrP(7‐34) or PTHrP antibodies reduced [ 3 H]thymidine incorporation in a dose‐dependent fashion in the highly tumorigenic cell line but did not affect the other lines. Thus, treatment with a PTH/PTHrP receptor antagonist reduced cell proliferation, suggesting that PTHrP signaling mediated by the phospholipase C (PLC) pathway stimulates proliferation of a highly tumorigenic immortalized breast epithelial cell line.