Parathyroid hormone-related protein (PTHrP) is widely expressed in primary breast tumours and is a cause of humoral hypercalcaemia of malignancy and is strongly implicated in their metastatic spread to bone. Overexpression of PTHRP and its receptor in breast tumour cells could also promote the growth of such cells in skeletal metastases by stimulating their proliferation in an autocrine fashion. Signal transduction of growth factor receptor, EGFR (ErbB1, HER1) and ErbB2 (Neu, HER2) receptor has been implicated in conferring resistance to traditional chemotherapy on cancer cells. Activation of extracellular-regulated kinase / mitogen-activated protein kinase (Erk/MAPK) is a critical signal transduction event-mediated cell proliferation, cell migration and tumor progression. In the present study, we examined the role of PTHrP-1-34, PTHrP-7-34 and PTHrP-1-86 in the Erk pathway in MCF7 breast carcinoma cell line with or without heregulinbeta1 (HRG beta1). MCF7 were transfected with pcDNA3/EGFR (erbB1) or with pcDNA3/erbB2 and treated overnight with 10nM of PTHrP-1-34, PTHrP-7-34, or PTHrP-1-86 and for 30min with 10ng of HRGbeta1 in serum free medium. PTHrP-1-34 significantly overexpressed ErbB1 and ErbB2 receptors compared with PTHrP-7-34 and PTHrP-1-86 treatment. Erk activity was significantly enhanced with HRG beta1 and PTHrP-1-34. But with PTHrP-7-34 and PTHrP-1-86, Erk activity was less significantly enhanced. Moreover, the level of protein kinase C, PKC found to be much higher with PTHrP-1-34 than PTHrP-7-34 and PTHrP-1-86 treated cells. However, the PKC was demolished in HRG beta1 treated cells and PKC activation had no effect on erbB1 and erbB2 induced Erk activation. Our results indicate that ErbB1 and erbB2 receptor induced Erk activation through the presence of HRG beta1 and PTHrP mitogenic effects are largely dependent on MAPKs, whose activity might be modulated by both Erk and PKC. This evaluation of downstream signaling could be crucial for PTHrP dependent growth-promoting effects in tumor progression.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]