During lactation, the PTHrP gene is highly expressed in mammary epithelial cells (MEC), and milk is the most abundant source of PTHrP in nature. Although the exact function of PTHrP during lactation remains unknown, it has been suggested that mammary-derived PTHrP circulates and participates in the regulation of calcium mobilization from the maternal skeleton and/or transport of calcium across MEC and into milk. In order to test this hypothesis, we used the cre/lox recombinase system to generate mice in which the PTHrP gene was disrupted only in MEC and only during lactation. Preliminary analysis of these mice suggested that withdrawal of PTHrP led to degeneration of lobuloalveolar structures in the lactating mammary gland and MEC apoptosis. This phenotype resembles the initial stages of mammary involution upon weaning, and analysis of PTHrP gene expression demonstrates that it is normally downregulated co- incident with the onset in involution. Therefore, our central hypothesis is that PTHrP serves two functions during lactation. The first is to act locally in a paracrine, autocrine or intracrine fashion to promote the survival of MEC during lactation. The second is to act systemically to participate in the regulation of maternal calcium homeostasis and to promote the mobilization of calcium from the maternal skeleton and its transport into milk. Reflecting this potential dual role, we propose two broad specific aims.
Specific Aim 1 seeks to examine the possibility that PTHrP supports MEC viability during lactation. We will characterize the nature of MEC cell death in the cre-lox model, examine the possibility that PTHrP acts via a nuclear pathway and explore the potential relationships between PTHrP and the RANKL/RANK/OPG system.
Specific Aim 2 seeks to determine if PTHrP regulates calcium transport and/or mobilization during lactation. We will use a cell culture system to investigate the potentially interrelated effects of PTHrP and the calcium-sensing receptor on calcium transport across MEC and will use the cre-lox model to determine if mammary-derived PTHrP, potentially interacting with IL-6, regulates maternal calcium and/or bone metabolism during lactation. We think the experiments outlined in this proposal should offer insight into the role of PTHrP during lactation.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA094175-03
Application #
6686421
Study Section
General Medicine B Study Section (GMB)
Program Officer
Sathyamoorthy, Neeraja
Project Start
2001-12-10
Project End
2006-11-30
Budget Start
2003-12-01
Budget End
2004-11-30
Support Year
3
Fiscal Year
2004
Total Cost
$291,030
Indirect Cost
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Kim, Wonnam; Takyar, Farzin M; Swan, Karena et al. (2016) Calcium-Sensing Receptor Promotes Breast Cancer by Stimulating Intracrine Actions of Parathyroid Hormone-Related Protein. Cancer Res 76:5348-60
Espina, Virginia; Wysolmerski, John; Edmiston, Kirsten et al. (2013) Attacking breast cancer at the preinvasion stage by targeting autophagy. Womens Health (Lond) 9:157-70
Mamillapalli, Ramanaiah; Wysolmerski, John (2010) The calcium-sensing receptor couples to Galpha(s) and regulates PTHrP and ACTH secretion in pituitary cells. J Endocrinol 204:287-97
VanHouten, Joshua N; Neville, Margaret C; Wysolmerski, John J (2007) The calcium-sensing receptor regulates plasma membrane calcium adenosine triphosphatase isoform 2 activity in mammary epithelial cells: a mechanism for calcium-regulated calcium transport into milk. Endocrinology 148:5943-54
Ardeshirpour, Laleh; Dann, Pamela; Adams, Douglas J et al. (2007) Weaning triggers a decrease in receptor activator of nuclear factor-kappaB ligand expression, widespread osteoclast apoptosis, and rapid recovery of bone mass after lactation in mice. Endocrinology 148:3875-86
VanHouten, Joshua N; Yu, Namyi; Rimm, David et al. (2006) Hypercalcemia of malignancy due to ectopic transactivation of the parathyroid hormone gene. J Clin Endocrinol Metab 91:580-3
Ardeshirpour, Laleh; Dann, Pamela; Pollak, Martin et al. (2006) The calcium-sensing receptor regulates PTHrP production and calcium transport in the lactating mammary gland. Bone 38:787-93
Hens, Julie R; Wilson, Kimberly M; Dann, Pamela et al. (2005) TOPGAL mice show that the canonical Wnt signaling pathway is active during bone development and growth and is activated by mechanical loading in vitro. J Bone Miner Res 20:1103-13
VanHouten, Joshua; Dann, Pamela; McGeoch, Grace et al. (2004) The calcium-sensing receptor regulates mammary gland parathyroid hormone-related protein production and calcium transport. J Clin Invest 113:598-608
Chu, Emily Y; Hens, Julie; Andl, Thomas et al. (2004) Canonical WNT signaling promotes mammary placode development and is essential for initiation of mammary gland morphogenesis. Development 131:4819-29

Showing the most recent 10 out of 14 publications