Parathyroid Hormone-related Protein and Transforming Growth Factor Activities in an Extract from a Breast Cancer Associated with Humoral Hypercalcemia of Malignancy

Abstract

The pathogeneses of hypercalcemia and hypophosphatemia which developed in a patient with metastatic invasive ductal breast carcinoma were studied. The patient had low plasma levels of immunoreactive parathyroid hormone (PTH) and 1,25(OH)2D, increased nephrogenous cyclic adenosine monophosphate (cAMP) excretion and low TmPO4/GFR, suggesting the presence of humoral PTH-like activity. The tumor extract showed activities which would stimulate bone resorption in vitro and cAMP generation in the osteogenic cell line, MC3T3 E1, and in the rat kidney cortex. In addition, the extract stimulated epidermal growth factor (EGF)-independent colony formation of the NRK 49F cells in soft agar, and inhibited the binding of EGF to A431 cells, indicating it to have transforming growth factor (TGF)-alpha activity. The extract contained appreciable amounts of immunoreactive PTH-related protein (PTH-rP) but negligible amounts of immunoreactive PTH. Thus, the PTH-like activity for stimulating cAMP generation in the bone and kidney was attributed to PTH-rP. Chromatographic analyses on reverse phase high performance liquid chromatography (HPLC) separated the PTH-rP activity from that of TGF-alpha and the bone resorbing activity in vitro was found only in the fractions of PTH-rP. It was concluded that this breast cancer produced PTH-rP as well as TGF-alpha, and the former was thought to have a major role to play in the humoral hypercalcemia of malignancy observed in this patient.