This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sanders, J. L. Articles by Brown, E. M. Search for Related Content PubMed PubMed Citation Articles by Sanders, J. L. Articles by Brown, E. M. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Compound via MeSH Substance via MeSH Medline Plus Health Information Breast Cancer Hazardous Substances DB CALCIUM COMPOUNDS CALCIUM, ELEMENTAL NEOMYCIN

Extracellular Calcium-Sensing Receptor Expression and Its Potential Role in Regulating Parathyroid Hormone-Related Peptide Secretion in Human Breast Cancer Cell Lines¹

Endocrine-Hypertension Division and Membrane Biology Program, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts 02115

Address all correspondence and requests for reprints to: Jennifer L. Sanders, Ph.D., Endocrine-Hypertension Division, Brigham and Women’s Hospital, 221 Longwood Avenue, Boston, Massachusetts 02115. E-mail: jsanders{at}rics.bwh.harvard.edu

Metastasis of breast cancer to bone occurs with advanced disease and produces substantial morbidity. Secretion of PTH-related peptide (PTHrP) from breast cancer cells is thought to play a key role in osteolytic metastases and is increased by transforming growth factor-ß (TGFß), which is released from resorbed bone. Elevated extracellular calcium (Ca_o²⁺) also stimulates PTHrP secretion from various normal and malignant cells, an action that could potentially be mediated by the Ca_o²⁺-sensing receptor (CaR) originally cloned from the parathyroid gland. Indeed, we previously showed that both normal breast ductal epithelial cells and primary breast cancers express the CaR. In this study we investigated whether the MCF-7 and MDA-MB-231 human breast cancer cell lines express the CaR and whether CaR agonists modulate PTHrP secretion. Northern blot analysis and RT-PCR revealed bona fide CaR transcripts, and immunocytochemistry and Western analysis with a specific anti-CaR antiserum demonstrated CaR protein expression in both breast cancer cell lines. Furthermore, elevated Ca_o²⁺ and the polycationic CaR agonists, neomycin and spermine, stimulated PTHrP secretion dose dependently, with maximal, 2.1- to 2.3-fold stimulation. In addition, pretreatment of MDA-MB-231 cells overnight with TGFß1 (0.2, 1, or 5 ng/ml) augmented both basal and high Ca_o²⁺-stimulated PTHrP secretion. Thus, in PTHrP-secreting breast cancers metastatic to bone, the CaR could potentially participate in a vicious cycle in which PTHrP-induced bone resorption raises the levels of Ca_o²⁺ and TGFß within the bony microenvironment, which then act in concert to evoke further PTHrP release and worsening osteolysis.

This article has been cited by other articles:

				Z. Saidak, R. Mentaverri, and E. M. Brown The Role of the Calcium-Sensing Receptor in the Development and Progression of Cancer Endocr. Rev., April 1, 2009; 30(2): 178 - 195. [Abstract] [Full Text] [PDF]

				R. Mamillapalli, J. VanHouten, W. Zawalich, and J. Wysolmerski Switching of G-protein Usage by the Calcium-sensing Receptor Reverses Its Effect on Parathyroid Hormone-related Protein Secretion in Normal Versus Malignant Breast Cells J. Biol. Chem., September 5, 2008; 283(36): 24435 - 24447. [Abstract] [Full Text] [PDF]

				G. J. Strewler Cancer Stem Cells and Bone Metastasis IBMS BoneKEy, September 1, 2008; 5(9): 308 - 322. [Abstract] [Full Text] [PDF]

				L. A Kingsley, P. G J Fournier, J. M Chirgwin, and T. A Guise Molecular Biology of Bone Metastasis Am. Assoc. Cancer Res. Educ. Book, April 12, 2008; 2008(1): 443 - 457. [Abstract] [Full Text] [PDF]

				L. A. Kingsley, P. G.J. Fournier, J. M. Chirgwin, and T. A. Guise Molecular Biology of Bone Metastasis Mol. Cancer Ther., October 1, 2007; 6(10): 2609 - 2617. [Abstract] [Full Text] [PDF]

				J. J. Wysolmerski Conversations Between Breast and Bone: Physiological Bone Loss During Lactation as Evolutionary Template for Osteolysis in Breast Cancer and Pathological Bone Loss After Menopause IBMS BoneKEy, August 1, 2007; 4(8): 209 - 225. [Abstract] [Full Text] [PDF]

				R. J. MacLeod, M. Hayes, and I. Pacheco Wnt5a secretion stimulated by the extracellular calcium-sensing receptor inhibits defective Wnt signaling in colon cancer cells Am J Physiol Gastrointest Liver Physiol, July 1, 2007; 293(1): G403 - G411. [Abstract] [Full Text] [PDF]

				P. M. Guerreiro, J. L. Renfro, D. M. Power, and A. V. M. Canario The parathyroid hormone family of peptides: structure, tissue distribution, regulation, and potential functional roles in calcium and phosphate balance in fish Am J Physiol Regulatory Integrative Comp Physiol, February 1, 2007; 292(2): R679 - R696. [Abstract] [Full Text] [PDF]

				J. Liao, A. Schneider, N. S. Datta, and L. K. McCauley Extracellular calcium as a candidate mediator of prostate cancer skeletal metastasis. Cancer Res., September 15, 2006; 66(18): 9065 - 9073. [Abstract] [Full Text] [PDF]

				G. J. Strewler The Stem Cell Niche and Bone Metastasis IBMS BoneKEy, May 1, 2006; 3(5): 19 - 29. [Abstract] [Full Text] [PDF]

				N. Chattopadhyay Effects of calcium-sensing receptor on the secretion of parathyroid hormone-related peptide and its impact on humoral hypercalcemia of malignancy Am J Physiol Endocrinol Metab, May 1, 2006; 290(5): E761 - E770. [Abstract] [Full Text] [PDF]

				M. A. Henderson, J. A. Danks, J. L. Slavin, G. B. Byrnes, P. F.M. Choong, J. B. Spillane, J. L. Hopper, and T. J. Martin Parathyroid Hormone-Related Protein Localization in Breast Cancers Predict Improved Prognosis Cancer Res., February 15, 2006; 66(4): 2250 - 2256. [Abstract] [Full Text] [PDF]

				G A Clines and T A Guise Hypercalcaemia of malignancy and basic research on mechanisms responsible for osteolytic and osteoblastic metastasis to bone Endocr. Relat. Cancer, September 1, 2005; 12(3): 549 - 583. [Abstract] [Full Text] [PDF]

				J. Tfelt-Hansen, P. Schwarz, E. F. Terwilliger, E. M. Brown, and N. Chattopadhyay Calcium-Sensing Receptor Induces Messenger Ribonucleic Acid of Human Securin, Pituitary Tumor Transforming Gene, in Rat Testicular Cancer Endocrinology, December 1, 2003; 144(12): 5188 - 5193. [Abstract] [Full Text] [PDF]

				J. Tfelt-Hansen, R. J. MacLeod, N. Chattopadhyay, S. Yano, S. Quinn, X. Ren, E. F. Terwilliger, P. Schwarz, and E. M. Brown Calcium-sensing receptor stimulates PTHrP release by pathways dependent on PKC, p38 MAPK, JNK, and ERK1/2 in H-500 cells Am J Physiol Endocrinol Metab, August 1, 2003; 285(2): E329 - E337. [Abstract] [Full Text] [PDF]

				R. J. MacLeod, N. Chattopadhyay, and E. M. Brown PTHrP stimulated by the calcium-sensing receptor requires MAP kinase activation Am J Physiol Endocrinol Metab, February 1, 2003; 284(2): E435 - E442. [Abstract] [Full Text] [PDF]

				J. Purroy and N. K. Spurr Molecular genetics of calcium sensing in bone cells Hum. Mol. Genet., October 1, 2002; 11(20): 2377 - 2384. [Abstract] [Full Text] [PDF]

				J. L. Sanders, N. Chattopadhyay, O. Kifor, T. Yamaguchi, and E. M. Brown Ca2+-sensing receptor expression and PTHrP secretion in PC-3 human prostate cancer cells Am J Physiol Endocrinol Metab, December 1, 2001; 281(6): E1267 - E1274. [Abstract] [Full Text] [PDF]