The parathyroid hormone-related protein receptor is expressed in breast cancer bone metastases and promotes autocrine proliferation in breast carcinoma cells

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 (Po0.05) 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.

PTHrP on MCF-7 breast cancer cells: a growth factor or an antimitogenic peptide?

“…Birch's group found a mitogenic effect of PTH and PTHrP on MCF-7 cells, with a parallel increase in cAMP intracellular levels. Therefore, the work by Hoey et al (2003) appears to support Birch's findings.…”

“…We read with interest the publication by Hoey et al (2003), on MCF-7 cell proliferation promoted by the overexpressed PTH/ PTHrP receptor, since a study on the effects of PTHrP on MCF-7 cell proliferation is currently in progress in our Lab.…”

Serum calcium and breast cancer risk: results from a prospective cohort study of 7,847 women

“…Calcium levels in serum may also be considered a marker for certain conditions, as calcium levels are increased following stimulation by PTH and vitamin-D. Experimental studies have shown that PTH have anti-apoptotic effects and may promote invasiveness [8][9][10], mechanisms that stimulate tumour growth. Contrary to this, vitamin-D may induce apoptosis, cell cycle arrest, and differentiation.…”

“…Experimental studies suggest that PTH has carcinogenic and tumour promoting effects [8][9][10]. At least three record-linkage studies have found a weak positive correlation between risk of breast cancer and primary hyperparathyroidism (pHPT), a condition with high PTH and often high calcium levels [11][12][13].…”

Identification, molecular characterization, and tissue expression of parathyroid hormone-related protein gene (PTHrP) from water buffalo (Bubalus bubalis)

“…Parathyroid hormone-related protein (PTHrP) was first identified in animal tumors and associated with malignant humoral hypercalcemia in 1987 (Moseley et al, 1987;Hoey et al, 2003). PTHrP is structurally related to parathyroid hormone (PTH) (Schlüter, 1999).…”