Parathyroid hormone-related protein (
PTHrP) was discovered as the
tumor product causing the
humoral hypercalcemia of malignancy. Its structural similarity to the
hormone, PTH, with 8 of the first 13
amino acids identical, was sufficient to explain the sharing by
PTHrP and PTH of a common receptor, PTH1R, although the remainder of the sequences are unique.
PTHrP has important roles in development of several organs, including breast and bone, and functions as a paracrine factor postnatally in these and other tissues. In addition to its hormonal role in
cancer,
PTHrP is produced by two thirds of primary breast
cancers and 90% of bone
metastases from
breast cancer, leading to the concept that its production in bone by
breast cancer cells promotes
bone resorption, thus favoring
tumor establishment and expansion, and an exit from
tumor dormancy in bone through downregulation of
leukemia inducing factor receptor (LIFR).
Cancer production of
PTHrP is increased by bone-derived
growth factors, with particular attention paid to TGFβ, as well as by promoter-driven transcriptional effects, such as the hedgehog signaling factor, GLI2, and microenvironment effects including changes in underlying stiffness of substrates for cells. Although interest has been focused on
PTHrP-induced
bone resorption in bone
metastasis, a mechanistically separate, protective effect against
tumor progression has been proposed. Although there is conflicting mouse data, there are clinical studies suggesting that increased production of
PTHrP by breast
cancers confers upon them a less invasive phenotype, an effect distinct from the
bone resorption-stimulating action that favors bone
metastasis.