Parathyroid hormone-related protein (PTHrP) in breast cancer: An auto-/paracrine growth factor? Studies on cells of the bone marrow microenvironment

Background: Breast cancer tissues express parathyroid hormone-related prote in (PTHrP) and as shown in previous studies the level of PTHrP expression i n the primary tumor correlates with the incidence of bone metastasis. Methods/Results: Analysing 49 primary breast cancer tissues by reverse tran scription based RT/PCR methods we found an expression of PTHrP in 48/49 pat ients with a coexpression of the PTH/PTHrP receptor in 42 patient samples. Coexpression of PTHrP and its receptor was also shown in all of five breast cancer cell lines MCF-7, MDA-MB-231, MDA-MB-468, DU 4475 and SK-BR-3. Looking for an autocrine growth modulating loop of PTHrP in breast cancer t hese cell lines were used as in vitro models for growth stimulation with hP THrP (1-40). The growth of MCF-7 and MDA-MB-468 as well as the cell line MD A-MB-231, which was unresponsive to exogenous PTHrP, was reduced by a neutr alizing monoclonal antibody against PTHrP. In all of the five breast cancer cell lines incubation with hPTHrP(1-40) led to a decrease in PTHrP express ion, whereas the expression of the PTH/PTHrP receptor was unchanged. Looking for paracrine sources of PTHrP in normal human bone marrow (bm) and peripheral blood (PB) we investigated hematopoietic and osteoblast cells. In hematopoietic cells only a low-level expression of PTHrP was detected by PCR analysis, by in situ hybridisation and immunocytology in the CD34(+) f raction of peripheral blood stem cell harvests of healthy allogeneic stem c ell donors and on the level of early hematopoietic progenitors in stem cell assays (CFU-A). In normal human osteoblast cells and cells of the osteobla st-like osteosarcoma cell line H0S58 expression of PTHrP was found by PCR b oth on day 1 and on day 32 of cell culture. Conclusion: In conclusion we documented an autocrine growth modulating loop for breast cancer cells by PTHrP, which might be fueled in a paracrine fas hion by osteoblasts and hematopoietic progenitor cells (CD34(+)) in the ear ly phase of breast cancer metastasis to the bone.