Enhanced growth of MCF-7 breast cancer cells overexpressing parathyroid hormone-related peptide

PTH-related peptide (PTHrP) is a secreted protein produced by breast cancer cells both in vivo and in vitro. Because of its structural similarity to P TH at the amino terminus, the two proteins interact with a common cell surf ace receptor, the PTH/PTHrP receptor. When overproduced by tumor cells, PTH rP enters the circulation, giving rise to the common paraneoplastic syndrom e of humoral hypercalcemia of malignancy. Although initially discovered in malignancies, PTHrP is now known to be produced by most cells and tissues i n the body. It acts as an autocrine and paracrine mediator of cell prolifer ation and differentiation, effects which are mediated via the PTH/PTHrP rec eptor. Recent evidence also has shown that, directly after translation, PTH rP is able to enter the nucleus and/or nucleolus and influence cell cycle p rogression and apoptosis. In this study, we have either overproduced PTHrP or inhibited endogenous PTHrP production in the breast cancer cell line, MC F-7. Overexpression of PTHrP was associated with an increase in mitogenesis , whereas inhibiting endogenous PTHrP production resulted in decreased cell proliferation. The overexpressed peptide targeted to the perinuclear space . In contrast, PTHrP interaction with the cell surface PTH/PTHrP receptor r esulted in decreased cell proliferation in the same cell line. This latter effect is dependent on interaction with the receptor, in that exogenously a dded PTHrP moieties known not to interact with the receptor had no effect o n cell growth. Furthermore, neutralization of added peptide with an anti-PT HrP antiserum completely abolished the growth inhibitory effects. In contra st, this antibody has no effect on the increased proliferation rate of the MCF-7 transfectants that overexpress PTHrP, compared with control cells. Th e net effect of autocrine/paracrine and intracrine effects of PTHrP in MCF- 7 cells overproducing the peptide is accelerated cell growth. These finding s have critical implications regarding the role of PTHrP in breast cancer, and they suggest that controlling PTHrP production in breast cancer may be useful therapeutically.