Parathyroid hormone-related protein in breast cancer tissues: Relationship between primary and metastatic sites

Abstract

The expression of parathyroid hormone-related protein (PTHrP) at primary and metastatic sites was studied retrospectively in specimens obtained at opreation and autopsy from 11 patients. The anti-human PTHrP monoclonal antibody, 4B3, was used in the immunohistochemical studies. The 11 cases showed metastases to the liver and the lung, and 9 showed bone metastases at autopsy. At primary sites, PTHrP was positive in the 9 cases with bone metastases, while the other 2 cases were negative for PTHrP. Regardless of the intensities of immunohistochemical staining of PTHrP at primary sites, cancer cells at metastatic sites in the liver and the lung were almost all negative for PTHrP. On the other hand, all PTHrP-positive cases at primary sites at operation showed skeletal metastases at autopsy, and the intensity of the immunohistochemical staining of PTHrP was strongly positive at all the sites of skeletal metastasis. These results suggest that while PTHrP is an important factor that causes cancer cells to erode and grow in skeletal bone, the expression of PHTrP is, concurrently, affected by an osseous microenvironment.

TGF-β in the Bone Microenvironment: Role in Breast Cancer Metastases

“…Initially, expression of PTHrP in the primary tumor appeared to be associated with formation of bone metastases [86,87]. In contrast, a large prospective study of 526 consecutive patients with operable breast cancer demonstrated that PTHrP expression in primary breast cancer was significantly associated with fewer (bone) metastases [84,[88][89][90]. Therefore, the most likely explanation for the observed increased PTHrP expression in breast cancer bone metastases [84,90], is that TGF-β in the bone microenvironment induces cancer cells to express PTHrP rather than cancer cells that metastasize to the bone having an intrinsically higher PTHrP expression.…”

A new human breast cancer cell line, KPL-3C, secretes parathyroid hormone-related protein and produces tumours associated with microcalcifications in nude mice

“…In other words, tumour-derived PTHrP acts as a circulating hormone like parathyroid hormone and induces hypercalcaemia. Recently, a series of studies has indicated that PTHrP is commonly expressed in breast cancer and that a higher expression of PTHrP may induce bone metastasis (Southby et al, 1990;Powell et al, 1991;Bundred et al, 1992;Vargus et al, 1992;Bouizar et al, 1993;Kohno et al, 1994a;Kohno et al, 1994b). It is conceivable that the PTHrP secreted by breast cancer cells, which exist in bone marrow, may act as a paracrine effector on osteoclasts, resulting in osteolytic involvement.…”

Study of RANKL Expression in Metastatic Breast Carcinoma

“…In vitro studies have demonstrated that breast cancer cells alone have the capacity to degrade the bone matrix, although these lesions of bone or dentine slices are not of the magnitude of those resulting from osteoclast-mediated bone destruction (Eilon and Mundy, 1978). Studies have also shown that PTHrP is expressed by the metastatic breast cancer cells and is a critical component in the mechanism of breast cancer metastases to bone (Boyce et al, 1999;Chirgwin and Guise, 2000;de la Mata et al, 1995;Guise, 1997;Guise et al, 1993;Henderson et al, 2001;Kohno et al, 1994;Thomas et al, 1999;Uy et al, 1995;Uy et al, 1997;Yoshida et al, 2000). Co-culture experiments have shown that breast cancer cells can produce both PTHrP and M-CSF which induce RANKL mRNA levels and inhibit OPG mRNA levels in osteoblasts in vitro (Mancino et al, 2001;Thomas et al, 1999).…”