The expression of parathyroid hormone-related protein in human breast cancer with skeletal metastases

Abstract

The relationship between the expression of parathyroid hormone-related protein (PTHrP) by breast cancer and skeletal metastases, was investigated using a monoclonal antibody against human PTHrP (4B3). The immunohistochemical localization of PTHrP was studied in sections of formalin-fixed, paraffin-embedded tissues from 28 breast cancers obtained surgically between 1980 and 1985. Of the 28 patients, 12 developed skeletal metastases, 8 developed lung metastases, and the other 8 were alive and disease-free at the time of this study. Sixteen of the 28 (57%) tumors showed positive immunoreactivity to 4B3, the PTHrP positive ratio being 83% in the patients who developed skeletal metastases, 38% in those who developed lung metastases, and 38% in those without recurrence, respectively. Thus, a significantly higher proportion of the patients who developed skeletal metastases were positive for PTHrP than the other two groups (P < 0.05). Furthermore, the level of positive staining was strongly related to positivity for estrogen and progesterone receptors (P < 0.01). These results are consistent with the hypothesis that PTHrP might be necessary for metastases to erode bone and grow in skeletal sites, and its expression could be related to certain hormones.

Hypercalcaemia of malignancy and basic research on mechanisms responsible for osteolytic and osteoblastic metastasis to bone

“…At least four other studies have confirmed these percentages, and one of these has demonstrated immunoreactive PTHrP within the cytoplasm of lobular and ductal epithelial cells in normal and fibrocystic breast tissues (Bundred et al 1991, Liapis et al 1993, Kohno et al 1994. Furthermore, 65-92% of hypercalcaemic breast cancer patients (with and without bone metastasis) had detectable plasma PTHrP concentration by radioimmunoassay similar to those documented in patients with HHM due to non-breast tumours (Bundred et al 1991, Grill et al 1991.…”

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.…”

Factors regulating the growth of metastatic cancer in bone.

“…Its expression by breast cancer cells appears to increase when the tumor cells metastasize to bone. For example, it has been detected by immunohistochemistry (Powell et al 1991, Kohno et al 1994 and in situ hybridization (Vargas et al 1992) in 80-90% of breast cancer metastases in bone, compared with only 38% in lung (Kohno et al 1994) and 17% (Powell et al 1991) in other non-bone sites. These findings suggest that PTHrP expression by breast cancer cells increases when they metastasize to bone and support a major potential role for tumor-produced PTHrP to mediate the increased bone resorption around osteolytic breast metastases.…”