ORIGINAL PAPER Role of PTHrP in Mammary Gland Development and Breast Cancer Minoti Hiremath • John Wysolmerski Published online: 4 July 2014 Ó Springer Science+Business Media New York 2014 Abstract Parathyroid hormone-related protein (PTHrP) signaling has been shown to affect the development of many tissues including bone, cartilage, and mammary gland. In this review, we focus on the role of PTHrP in the normal mammary gland and its contributions to breast pathogenesis. During embryonic mammary development, PTHrP drives mammary mesenchyme specification, which is responsible for maintaining mammary cell fate, pro- moting the outgrowth of ducts, and directing the formation of the nipple. During lactation, PTHrP mobilizes maternal calcium to ensure a supply of calcium into milk and may play a role in regulating neonatal bone and mineral metabolism. PTHrP is expressed in primary breast cancer and breast cancer metastases, and contributes to the for- mation of osteolytic bone lesions as well as the growth and progression of primary tumors. Keywords PTHrP Á Mammary Á Breast cancer Á Calcium Á Bone Á Osteolytic metastasis Abbreviations HHM Humoral hypercalcemia of malignancy PTH Parathyroid hormone PTHrP Parathyroid hormone-related protein TEBs Terminal end buds PTH1R Type 1 PTH/PTHrP receptor BMP Bone morphogenic protein BMPR1a Bone morphogenic protein receptor, type 1a CaSR Calcium-sensing receptor Introduction Parathyroid hormone-related protein (PTHrP) was discov- ered as the cause of a common paraneoplastic syndrome known as humoral hypercalcemia of malignancy (HHM). It derives its name from structural and functional similarities with parathyroid hormone (PTH), and the PTHrP gene (official gene symbol is Pthlh) is a member of a small family of related genes that include Pthlh, PTH, and tu- buloinfundibular peptide of 39 amino acids (TIP-39) [1]. As a result of a high degree of homology in the amino- terminal portions of PTH and PTHrP (eight of the first 13 amino acids are identical), both proteins can bind and signal through the same G-protein-coupled receptor, known as the type 1 PTH/PTHrP receptor (PTH1R) [2]. PTH is produced almost exclusively by the parathyroid glands and is secreted into the systemic circulation to act as a classical peptide hormone. In contrast, PTHrP is expressed widely, particularly during embryonic develop- ment, and it acts as a local autocrine/paracrine/intracrine growth factor. PTHrP has been shown to have important biological functions in many tissues including bone, car- tilage, and the mammary gland [3, 4]. In this review, we will summarize the functions of PTHrP during mammary development, its role in lactational physiology, and its contributions to breast pathophysiology, especially breast cancer. PTHrP’s Role in the Embryonic Mammary Gland In the mouse embryo, mammary gland development begins with the formation of raised epithelial ridges called the mammary lines that extend between the limb buds on each M. Hiremath Á J. Wysolmerski (&) Department of Internal Medicine, Yale University, New Haven, CT, USA e-mail: john.wysolmerski@yale.edu 123 Clinic Rev Bone Miner Metab (2014) 12:178–189 DOI 10.1007/s12018-014-9170-9