Parathyroid Hormone-Related Protein Specifies the Mammary Mesenchyme and Regulates Embryonic Mammary Development
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Parathyroid Hormone-Related Protein Specifies the Mammary Mesenchyme and Regulates Embryonic Mammary Development Minoti Hiremath & John Wysolmerski Received: 4 March 2013 / Accepted: 16 April 2013 / Published online: 3 May 2013 # Springer Science+Business Media New York 2013
Abstract Parathyroid Hormone related Protein (PTHrP) is a critical regulator of mammary gland morphogenesis in the mouse embryo. Loss of PTHrP, or its receptor, PTHR1, results in arrested mammary buds at day 15 of embryonic development (E15). In contrast, overexpression of PTHrP converts the ventral epidermis into hairless nipple skin. PTHrP signaling appears to be critical for mammary mesenchyme specification, which in turn maintains mammary epithelial identity, directs bud outgrowth, disrupts the male mammary rudiment and specifies the formation of the nipple. In the embryonic mammary bud, PTHrP exerts its effects on morphogenesis, in part, through epithelialstromal crosstalk mediated by Wnt and BMP signaling. Recently, PTHLH has been identified as a strong candidate for a novel breast cancer susceptibility locus, although PTHrP’s role in breast cancer has not been clearly defined. The effects of PTHrP on the growth of the embryonic mammary rudiment and its invasion into the dermis may, in turn, have connections to the role of PTHrP in breast cancer. Keywords PTHrP . Mammary . Development . Embryonic . Breast . Wnt . Bmp Abbreviations PTHrP Parathyroid hormone related protein K14 Keratin 14 PTHR1 Parathyroid hormone receptor, type I M. Hiremath S-128 Department of Biological Sciences, Boise State University, 1910 University Drive, Boise, ID 83725, USA J. Wysolmerski (*) Department of Internal Medicine, Yale University School of Medicine, S120 TAC, 300 Cedar Street, New Haven, CT 06520, USA e-mail: [email protected]
WT AR ER BMP MMP
Wild-type Androgen receptor Estrogen receptor Bone morphogenic protein Matrix metalloprotease
Introduction Parathyroid hormone-related protein (PTHrP) derives its name from structural and functional similarities with parathyroid hormone (PTH) [1]. Both PTH and PTHrP are derived from the same ancestral gene and are highly homologous in their amino-terminal domains [2]. As a result, both PTH and PTHrP bind and signal through the same G-protein coupled receptor, known as the Type 1 PTH/PTHrP receptor (PTHR1) [3]. While PTH is secreted almost exclusively by the parathyroid glands, PTHrP is expressed widely. During normal embryonic and postnatal development, PTHrP acts as a local autocrine/paracrine/intracrine growth factor in many tissues including bone, cartilage and the mammary gland [4]. Unlike PTH, which acts as a classical peptide hormone, PTHrP does not normally circulate. The exceptions to this rule include lactation and patients with cancer, including breast cancer. During lactation, circulating PTHrP mobilizes skeletal calcium stores to be delivered to the breast for milk production. In some patients with cancer, PTHrP, secreted by malignant cells, mobilizes skeletal calcium to cause humoral hypercal
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