title: Calcium-Sensing Receptor Promotes Breast Cancer by Stimulating Intracrine Actions of Parathyroid Hormone-Related Protein.
abstract: Parathyroid hormone-related protein (PTHrP) contributes to the development and metastatic progression of breast cancer by promoting hypercalcemia, tumor growth, and osteolytic bone metastases, but it is not known how PTHrP is upregulated in breast tumors. Here we report a central role in this process for the calcium-sensing receptor, CaSR, which enables cellular responses to changes in extracellular calcium, through studies of CaSR-PTHrP interactions in the MMTV-PymT transgenic mouse model of breast cancer and in human breast cancer cells. CaSR activation stimulated PTHrP production by breast cancer cells in vitro and in vivo Tissue-specific disruption of the casr gene in mammary epithelial cells in MMTV-PymT mice reduced tumor PTHrP expression and inhibited tumor cell proliferation and tumor outgrowth. CaSR signaling promoted the proliferation of human breast cancer cell lines and tumor cells cultured from MMTV-PyMT mice. Further, CaSR activation inhibited cell death triggered by high extracellular concentrations of calcium. The actions of the CaSR appeared to be mediated by nuclear actions of PTHrP that decreased p27(kip1) levels and prevented nuclear accumulation of the proapoptotic factor apoptosis inducing factor. Taken together, our findings suggest that CaSR-PTHrP interactions might be a promising target for the development of therapeutic agents to limit tumor cell growth in bone metastases and in other microenvironments in which elevated calcium and/or PTHrP levels contribute to breast cancer progression. Cancer Res; 76(18); 5348-60. ©2016 AACR.
authors.affiliation: Section of Endocrinology and Metabolism, Department of Internal Medicine, Yale University School of Medicine, New Haven Connecticut.
authors.forename: Wonnam
authors.initials: W
authors.lastname: Kim
authors.affiliation: Section of Endocrinology and Metabolism, Department of Internal Medicine, Yale University School of Medicine, New Haven Connecticut.
authors.forename: Farzin M
authors.initials: FM
authors.lastname: Takyar
authors.affiliation: Section of Endocrinology and Metabolism, Department of Internal Medicine, Yale University School of Medicine, New Haven Connecticut.
authors.forename: Karena
authors.initials: K
authors.lastname: Swan
authors.affiliation: Section of Endocrinology and Metabolism, Department of Internal Medicine, Yale University School of Medicine, New Haven Connecticut.
authors.forename: Jaekwang
authors.initials: J
authors.lastname: Jeong
authors.affiliation: Section of Endocrinology and Metabolism, Department of Internal Medicine, Yale University School of Medicine, New Haven Connecticut.
authors.forename: Joshua
authors.initials: J
authors.lastname: VanHouten
authors.affiliation: Section of Endocrinology and Metabolism, Department of Internal Medicine, Yale University School of Medicine, New Haven Connecticut.
authors.forename: Catherine
authors.initials: C
authors.lastname: Sullivan
authors.affiliation: Section of Endocrinology and Metabolism, Department of Internal Medicine, Yale University School of Medicine, New Haven Connecticut.
authors.forename: Pamela
authors.initials: P
authors.lastname: Dann
authors.affiliation: Cancer Epidemiology Program, University of Hawaii Cancer Center, University of Hawaii School of Medicine, Honolulu, Hawaii.
authors.forename: Herbert
authors.initials: H
authors.lastname: Yu
authors.affiliation: Section of Endocrinology, Diabetes and Bone Disease, Department of Medicine, Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Fiaschi-Taesch
authors.affiliation: Endocrine Unit, San Francisco and Veteran Affairs Medical Center, University of California, San Francisco, California.
authors.forename: Wenhan
authors.initials: W
authors.lastname: Chang
authors.affiliation: Section of Endocrinology and Metabolism, Department of Internal Medicine, Yale University School of Medicine, New Haven Connecticut. john.wysolmerski@yale.edu.
authors.forename: John
authors.initials: J
authors.lastname: Wysolmerski
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D015151:Immunoblotting; D051379:Mice; D018345:Mice, Knockout; D044162:Parathyroid Hormone-Related Protein / Q000378:metabolism*; D044169:Receptors, Calcium-Sensing / Q000378:metabolism*; D046888:Tissue Array Analysis
chemical_list: D044162:Parathyroid Hormone-Related Protein; D044169:Receptors, Calcium-Sensing