Parathyroid hormone-related peptide (PTHrP) is a secreted protein produced by a variety of human cancers, including breast, prostate, lung, and renal carcinomas. Because of its structural similarity to parathyroid hormone at the amino terminus, the two proteins interact with a common cell surface receptor, the PTH/PTHrP receptor. When overproduced by tumor cells, PTHrP enters the circulation, giving rise to the common paraneoplastic syndrome of Humoral Hypercalcemia of Malignancy (HHM). Although initially discovered in malignancies, PTHrP is now known to be produced by most cells and tissues in the body. It acts as an autocrine and paracrine mediator of cell proliferation and differentiation, effects which are mediated via the PTH/PTHrP receptor. Recent evidence also has shown that, directly following translation, PTHrP is able to enter the nucleus and/or nucleolus and influence cell cycle progression and apoptosis (intracrine effects). We are studying the effects of PTHrP on cell proliferation of breast cancer cells. These studies are being addressed in two ways. In order to study the autocrine/paracrine effects of the peptide, full-length PTHrP has been over-expressed in a bacterial system and purified to homogeneity. In order to study the intracrine effects, PTHrP cDNA has been cloned in an expression vector and stably transfected in breast cancer cells . We have shown that PTHrP localizes to the nucleus and produces a net increase in breast cancer cell proliferation. The mechanism for this effect is being investigated with respect to cell cycle regulation.
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