Parathyroid Hormone–Related Protein Localization in Breast Cancers Predict Improved Prognosis

Abstract

In a prospective study of 526 consecutive patients with operable breast cancer, the significance of positive parathyroid hormone-related protein (PTHrP) staining by immunohistology has been evaluated for a median of 10-year follow-up. Improved survival was observed for the 79% of tumors which stained positively for PTHrP [estimated univariate hazard ratio, 0.43; 95% confidence interval (95% CI), 0.30-0.62; P < 0.001]. Adjustments for N stage, progesterone receptor status, and log tumor size changed this estimate only slightly to 0.47 (95% CI, 0.63-0.69; P = 0.001). Patients with PTHrP-positive primary tumors were less likely to develop bone metastases (hazard ratio, 0.63; 95% CI, 0.41-0.98; P = 0.04). PTHrP status was associated with estrogen receptor (P = 0.01), progesterone receptor (P = 0.03), and menopausal status (P = 0.006) but was not significantly associated with tumor size, vascular invasion, tumor grade, or patient age. Of 19 patients requiring surgery for bone metastases, the primary cancers were PTHrP negative in seven, all but one of whom had PTHrP-positive bone metastases. All 12 patients with PTHrP-positive primary cancers also had positive bone metastases. We conclude that increased production of PTHrP by breast cancers confers on them a less invasive phenotype, an effect distinct from the bone resorption-stimulating action that favors bone metastasis. It is likely that the latter property is influenced by factors in the bone microenvironment. (Cancer Res 2006; 66(4): 2250-6)

Impact of Chemotherapy on Hypercalcemia in Breast and Lung Cancer Patients

“…PTHrP levels have been reported to be increased in 33-84% of breast cancer and 46-47% of lung cancers (Clines, 2011). In a prospective study, Henderson et al (2006) studied 526 breast cancer patients whose PTHrP level was monitored for 10 years by using immunohistology (Henderson et al, 2006).…”

“…While solid cancers with bone or other organs metastases were found to have negative PTHrP secretion, which led the authors to conclude that breast cancer patient who had a positive PTHrP production were characterized by non invasive phenotype. The study by Henderson et al (2006) antagonized the old hypothesis that PTHrP found with primary breast cancer stages will increases the likelihood of development of skeletal metastases. PTHrP is the main factor in incidence and/or severity of hypercalcemia (Henderson et al, 2006).…”

“…The study by Henderson et al (2006) antagonized the old hypothesis that PTHrP found with primary breast cancer stages will increases the likelihood of development of skeletal metastases. PTHrP is the main factor in incidence and/or severity of hypercalcemia (Henderson et al, 2006).…”

“…PTHrP levels are also associated with the onset of hypercalcemia in breast cancer patients without bone metastases (Henderson et al, 2006).…”

Methylation of specific CpG sites in the P2 promoter ofparathyroid hormone-related proteindetermines the invasive potential of breast cancer cell lines

“…PTHrP expression assessed by immunohistochemistry correlated with increasing histological grade, shorter overall or disease-free survival in some studies 30,31 while other studies found no correlation at all 32 or even a correlation with improved survival and a less invasive phenotype. 33 Most of the studies so far performed have concentrated on immunohistochemistry to assess the expression status of PTHrP and little is known about the molecular mechanisms that lead to PTHrP overexpression. Alternative transcription of the PTHrP gene arises from three distinct promoters: P1 and P3 are canonical TATA box-dependent promoters, while P2 is a GC-rich promoter.…”