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7. Distinct, Tissue-Specific Regulation of Vitamin D Receptor in the Intestine, Kidney, and Skin by Dietary Calcium and Vitamin D

Author

Rizk-Rabin Marthe, Bouizar Zhor, Walrant Odile, and Rougui Zineb

Subjects
Keratinocytes, Male, musculoskeletal diseases, medicine.medical_specialty, Duodenum, Population, chemistry.chemical_element, Lactose, Calcium, Biology, Kidney, Calcitriol receptor, vitamin D deficiency, Endocrinology, Calcitriol, Internal medicine, polycyclic compounds, medicine, Vitamin D and neurology, Animals, RNA, Messenger, Rats, Wistar, Vitamin D, education, education.field_of_study, digestive, oral, and skin physiology, Kidney metabolism, Vitamin D Deficiency, medicine.disease, Immunohistochemistry, Vitamin D-dependent calcium-binding protein, Diet, Rats, Calcium, Dietary, Gene Expression Regulation, chemistry, Vitamin D3 Receptor, Receptors, Calcitriol, lipids (amino acids, peptides, and proteins), Epidermis
Abstract

We studied the effects of vitamin D deficiency and its correction by vitamin D or calcium-lactose supplementation on vitamin D receptor (VDR) expression in skin keratinocytes, kidney, and duodenum of adult rats. VDR messenger RNA (mRNA) was assayed by Northern blot, and VDR protein was determined immunocytochemically. In addition, four subpopulations of keratinocytes were isolated, characterized for their stages of differentiation, and analyzed for VDR expression. Vitamin D deficiency decreased VDR mRNA in all three tissues. Treatment with vitamin D or calcium-lactose reestablished the VDR mRNA content of the epidermis, but not that of the kidneys, and only the calcium-lactose diet increased duodenal VDR mRNA. The regulation of VDR mRNA in the epidermis was independent of cell differentiation, whereas VDR protein varied with differentiation. The VDR-positive cells in the control rats were at early and advanced states of differentiation. The expression of VDR was decreased by vitamin D deficiency and returned to control values after vitamin D or calcium supplementation. Vitamin D treatment, but not calcium, induced VDR expression in the normally immature population. Vitamin D and calcium, therefore, have distinct, tissue-specific effects on VDR. In epidermis, the posttranscriptional regulation of VDR expression is linked to cell differentiation. Calcium may be a key factor for VDR transcription, whereas both vitamin D and calcium seem to contribute to its posttranscriptional regulation.

Published
1998
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9. PTHrP, calcitonin and calcitriol in a case of severe, protracted and refractory hypercalcemia due to a pancreatic neuroendocrine tumor

Author

Van den Eynden, Gert, Neyret, Aymeric, Fumey, Glawdys, Rizk-Rabin, Marthe, Vermeulen, Peter B., Bouizar, Zhor, Body, Jean-Jacques, Dirix, Luc Y, Van den Eynden, Gert, Neyret, Aymeric, Fumey, Glawdys, Rizk-Rabin, Marthe, Vermeulen, Peter B., Bouizar, Zhor, Body, Jean-Jacques, and Dirix, Luc Y

Abstract

A patient with a primary neuroendocrine tumor of the pancreas, presented with severe hypercalcemia. This hypercalcemia of malignancy (HCM) failed to respond to intensive bisphosphonate treatment and needed continuous enhanced diuresis. Only after successful antitumor therapy did the hypercalcemia subside. Hypercalcemia was associated with increased concentrations of plasma PTHrP, calcitonin and 1,25-(OH)2D3. Bone mineral density was markedly increased. We demonstrated the presence of both PTHrP and calcitonin in the tumor at the mRNA and protein level, using RT-PCR, immunohistochemistry and Western blotting. The high levels of plasma PTHrP and the demonstrated predominant renal mechanism in this case of HCM are suspected to be the cause for its refractoriness to bone resorption inhibitors. Our findings furthermore suggest that the tumoral production of calcitonin and PTHrP might have contributed to the increased bone mineral storage of calcium and thus probably attenuated the development of frank hypercalcemia. © 2006 Elsevier Inc. All rights reserved., SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2007

11. Synthesis of and response to 1,25 dihydroxycholecalciferol by subpopulations of murine epidermal keratinocytes: existence of a paracrine system for 1,25 dihydroxycholecalciferol

Author

Pavlovitch Jana, Garabedian Michele, Marthe Rizk-Rabin, Bouizar Zhor, and Rougui Zineb

Subjects
Keratinocytes, medicine.medical_specialty, Cell division, Physiology, Cellular differentiation, Clinical Biochemistry, Biology, Cell morphology, Tritium, Paracrine signalling, Calcitriol, Internal medicine, medicine, Animals, RNA, Messenger, Rats, Wistar, Receptor, Cells, Cultured, Epidermis (botany), Cell Cycle, Cell Differentiation, Cell Biology, Flow Cytometry, Immunohistochemistry, Cell biology, Rats, Endocrinology, medicine.anatomical_structure, Epidermal Cells, Cell culture, Receptors, Calcitriol, Rabbits, Keratinocyte, Cell Division
Abstract

The epidermis is both a target tissue for and a source of 1,25 dihydroxycholecal-ciferol. The present study determines which of the epidermal cell populations synthesizes 1,25 dihydroxycholecalciferol and which responds to this hormone. Epidermal keratinocytes from new born rat epidermis were separated by unit gravity sedimentation into poorly differentiated cells, slow-cycling more differentiated cells, actively proliferating cells, and terminally differentiating subpopulations. The keratinocyte populations were characterized by cell size analysis, cell morphology, and DNA and RNA contents (acridine orange flow cytometry). 1,25(OH)2D3 synthesis was studied by measuring the conversion of [3H] 25(OH)D3 to [3H] 1,25(OH)2D3. The purified product was tested for its ability to compete with synthetic [3H] 1,25(OH)2D3 for binding to chick intestinal cytosol. The responses of the keratinocyte subpopulations to exogeneous 1,25(OH)2D3 were evaluated by the increase in 25(OH)D3-24 hydroxylase activity. Furthermore the expression of 1,25(OH)2D3 receptors (VDR) was examined in these cell populations. The results show that only the least differentiated cells produced 1,25(OH)2D3. In contrast, immunocytochemical detection of VDR, the VDR mRNA, and a 25(OH)D3-24 hydroxylase response to 1,25(OH)2D3 were mainly found in the more differentiated cells. Thus, the ability of epidermis to synthesize 1,25(OH)2D3 and be simultaneously sensitive to it depends on the state of cell differentiation. This suggests that the mammalian epidermis contains a paracrine system in which the more differentiated keratinocytes are sensitive to the 1,25(OH)2D3 produced locally by neighboring immature ones. © 1994 wiley-Liss, Inc.

Published
1994

14. Differential Expression of Parathyroid Hormone–Related Protein in Adrenocortical Tumors: Autocrine/Paracrine Effects on the Growth and Signaling Pathways in H295R Cells

Author

Rizk-Rabin, Marthe, primary, Assie, Guillaume, additional, Rene-Corail, Fernande, additional, Perlemoine, Karine, additional, Hamzaoui, Hinda, additional, Tissier, Fréderique, additional, Lieberherr, Michele, additional, Bertagna, Xavier, additional, Bertherat, Jerome, additional, and Bouizar, Zhor, additional

Published
2008
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22. Methylation of specific CpG sites in the P2 promoter of parathyroid hormone-related proteindetermines the invasive potential of breast cancer cell lines

Author

Tost, Jörg, Hamzaoui, Hinda, Busato, Florence, Neyret, Aymeric, Mourah, Samia, Dupont, Jean-Michel, and Bouizar, Zhor

Abstract

Parathyroid hormone-related protein(PTHrP) is upregulated in primary breast cancers and a major candidate for osteoclastic bone resorption present at sites of breast cancer to bone metastases. Using a human model of mammary epithelial cell lines differing in tumorigenicity and PTHrPexpression, we investigated the role of epigenetic modifications for PTHrPexpression. Quantitative analysis of the DNA methylation patterns at a total of 104 CpGs in the promoter region of PTHrP by pyrosequencing showed the absence of methylation in all analyzed cell lines in the large CpG island upstream of exon 1C. In the second intron of promoter 2 (P2) a region was identified containing 4 CpG nucleotides for which differential methylation correlated with the PTHrP expression level. The functional importance of this control mechanism was confirmed by the ability of the demethylating agent 5'-azacytidine to induce PTHrPmRNA and iPTHrP protein expression in previously non-expressing cell lines and increase their production by metastatic NS2T2A1 cells. In particular, transcription from P2 was activated non-tumoral S1T3 cells upon treatment with 5'-azacytidine. Our findings support the hypothesis that the methylation status of specific CpG dinucleotides is the dominant mechanism involved in silencing of PTHrPexpression rather than the overall methylation of the CpG island. Methylation of the PTHrPP2 is a potential marker of breast cancer progression and might be used to evaluate the metastatic potential of breast tumors.

Published
2011
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23. Purification and characterization of calcitonin receptors in rat kidney membranes by covalent cross-linking techniques.

Author

Bouizar, Zhor, Fouchereau-Peron, Martine, Taboulet, Jacqueline, Moukhtar, Mohsen S., and Milhaud, Gerard

Subjects
*CALCITONIN, *LABORATORY rats, *KIDNEY diseases, *MOLECULAR sieves, *ORGANIC compounds, *POLYACRYLAMIDE
Abstract

We have characterized the binding parameters of renal receptors (Scatchard analysis revealed the presence of two binding sites: site I, Ka1 = 1.29 X 109 M-1, number of binding sites = 9.9 X 106/μg protein; site II, Ka2 = 0.93 X 108 M-1, number of binding sites = 4.27 X 108/μg protein) and studied the effect of solubilization. The high-affinity sites are preserved during affinity chromatography and the process results in a 6080-fold purification of those sites. The lower-affinity sites are also preserved but the overall purification factor is about 40% lower than that obtained using molecular sieving. The purification of the renal calcitonin receptor by molecular sieving (Sephacryl S-200) is accompanied by total loss of the high-affinity site; however, the low-affinity site is enriched over 1642-fold. Binding parameters were obtained for the purified fractions. Synthetic salmon calcitonin was also bound to renal membranes using the bifunctional reagent disuccinimidyl suberate and photo-affinity cross-linking using hydroxysuccinimidyl azidobenzonate reagent. Cross-linked receptor eluted in the same volume as solubilized membranes specifically binding salmon calcitonin (S-200 chromatography). Sodium dodecyl sulfate polyacrylamide gel electrophoresis analysis of purified fractions showed several protein bands with apparent molecular masses ranging from 18000 Da to 100000 Da in the presence or absence of a reducing agent (2-mercaptoethanol). Autoradiography of polyacrylamide gels of cross-linked calcitonin receptor showed only three protein bands specifically binding salmon calcitonin, Their molecular masses were 70000 Da, 40000 Da and 33000 Da respectively. The 40000-Da molecule represents a major band (47% total binding species). This suggests that these three proteins are the principal components of the calcitonin receptor and that S-S bonds are not involved in the assembly of the receptor subunits. [ABSTRACT FROM AUTHOR]

Published
1986
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25. Parathyroid Hormone-Related Protein in an Esophageal Squamous Cell Carcinoma with Tumor-Induced Hypercalcemia.

Author

J&aauml;is, Philippe, Bouizar, Zhor, Binn, Muriel, Vissuzaine, Christiane, Hayem, Gilles, Mignon, Michel, and Lewin, Miguel J. M.

Subjects
SQUAMOUS cell carcinoma, IMMUNOHISTOCHEMISTRY, HYPERCALCEMIA, MUCOUS membranes, METASTASIS
Abstract

Cancers from patients with tumor-induced hypercalcemia usually produce a circulating factor that mimics the parathyroid hormone activity, termed parathyroid hormone-related protein. Incidence of tumor-induced hypercalcemia appears to be high in patients with squamous cell carcinoma of the esophagus., and the presence of parathyroid hormone-related protein have been shown in some primary esophageal cancers. In the present study, we have investigated the presence of parathyroid hormone-related protein in a patient with metastased squamous cell carcinoma of the esophagus complicated with tumor-induced hypercalcemia. Protein was searched by immunohistochemistry., and messenger RNA was investigated by reverse transcriptase-polymerase chain reaction and S1 nuclease assay. Both messenger RNA and protein were detected in hepatic metastases, whereas normal esophageal mucosa and primary cancer did not express detectable protein or messenger RNA using the S1 nuclease assay. Reverse transcriptase-polymerase chain reaction was positive in all these tissues, including normal esophageal mucosa. In conclusion, the present case suggests that tumor-induced hypercalcemia due to esophageal squamous cell carcinoma may he caused by parathyroid hormone-related protein mostly released by liver metastases. [ABSTRACT FROM AUTHOR]

Published
1997

26. The Parathyroid Hormone–Related Protein (PTHrP) Gene: Use of Downstream TATA Promotor and PTHrP 1–139 Coding Pathways in Primary Breast Cancers Vary with the Occurrence of Bone Metastasis

Author

Dr. Bouizar, Zhor, Spyratos, Frederique, and De vernejoul, Marie‐Christine

Abstract

We analyzed the use of different promoters and the splicing patterns of the exons encoding 5′‐ and 3′‐untranslated sequence amounts of parathyroid hormone–related protein (PTHrP) gene products in breast cancers. Tumor samples from 74 cases of primary breast cancer that had been followed from 1 to 14 years were selected retrospectively according to the occurrence of metastasis: 18 patients developed no metastasis (NM), 56 developed metastases (M), 22 of whom developed metastases in soft tissues (MB−) and 34 of whom developed bone metastases (MB+). The amount of the 1–139 isoform mRNA was much higher in the tumors of patients who later developed metastases (M: 0.29 ± 0.03) than in those of patients who developed no metastases (NM, 0.13 ± 0.03; p< 0.01). This isoform mRNA was also more abundant in breast tumors from patients who developed bone metastases (MB+, 0.39 ± 0.04) than in those of patients who developed metastases in soft tissues (MB−, 0.15 ± 0.03; p< 0.0001). By contrast, the amounts of the 1–141 isoform mRNA in these three groups of tumors were similar, but its concentration was higher in the tumors of premenopausal women than in those of postmenopausal women (p< 0.05). Analysis with 5′ untranslated regions‐specific primers showed transcription from all three putative transcription start sites of PTHrP (P1, P2, and P3). The P3‐initiated transcripts were more abundant in patients who developed metastases (M, 0.31 ± 0.03) than in the nonmetastatic tumors (NM, 0.13 ± 0.03; p< 0.01). The amount of P3 element did not differ with the site of metastasis (BM+, 0.32 ± 0.05; BM−, 0.28 ± 0.05; NS). The same trend was observed for the P2 element. However, the use of P2‐initiated messages was strongly associated with the absence of estrogen receptors from the breast tumors (p< 0.01). We thus find a close association between the pattern of PTHrP gene expression and the outcome of breast cancer. The P3‐initiated start site and the presence of PTHrP 139 mRNA could help identify patients at risk of developing metastases.

Published
1999
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28. Differential expression of parathyroid hormone-related protein in adrenocortical tumors: autocrine/paracrine effects on the growth and signaling pathways in H295R cells

Author

Fernande René-Corail, Karine Perlemoine, Marthe Rizk-Rabin, Xavier Bertagna, Frédérique Tissier, Jérôme Bertherat, Michèle Lieberherr, Guillaume Assié, Z. Bouizar, Hinda Hamzaoui, Institut Cochin (UMR_S567 / UMR 8104), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), Pôle Endocrinologie-Diabétologie Adultes-Enfants, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Cochin [AP-HP]-Hôpital Saint-Vincent de Paul, Nutrition et Régulation Lipidique des Fonctions Cérébrales, Institut National de la Recherche Agronomique (INRA), Service de biochimie-hormonologie [Béclère], Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Antoine Béclère, This study was supported in part by Plan Hospitalier de Recherche Clinique (PHRC) grant (AOM 06 179 to the Comete Network coordinated by Prof. P.F. Plouin) and by grants from INSERM and the Ministère Délégué à la Recherche et des Nouvelles Technologies. H. Hamzaoui was the recipient of fellowships from the Cancer & Solidarity Foundation, the Association pour la Recherche contre le Cancer (ARC) and the Fondation pour la Recherche Médicale (FRM)., Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) - CHU Cochin [AP-HP] - Hôpital Saint-Vincent de Paul, Université Paris-Sud - Paris 11 (UP11) - Assistance publique - Hôpitaux de Paris (AP-HP) - Hôpital Antoine Béclère, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Saint-Vincent de Paul, AP-HP - Hôpital Antoine Béclère [Clamart], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11), Bouizar, Zhor, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Antoine Béclère [Clamart], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
Male, MESH: Signal Transduction, MESH : RNA, Messenger, Epidemiology, MESH : Aged, MESH : Adrenal Cortex Neoplasms, Apoptosis, MESH: Cell Cycle, MESH : Blotting, Western, MESH: Adrenal Cortex Neoplasms, Metastasis, 0302 clinical medicine, MESH: Reverse Transcriptase Polymerase Chain Reaction, MESH : Female, Receptor, MESH: Aged, 0303 health sciences, MESH : Prognosis, MESH: Middle Aged, Reverse Transcriptase Polymerase Chain Reaction, Paracrine cAMP, Cell Cycle, MESH : Reverse Transcriptase Polymerase Chain Reaction, Middle Aged, MESH : Adult, Prognosis, musculoskeletal system, 3. Good health, Blot, MESH : Cyclic AMP-Dependent Protein Kinases, qPCR, Oncology, 030220 oncology & carcinogenesis, MESH: Calcium, Female, Signal transduction, PTHrP Receptor, MESH : Parathyroid Hormone-Related Protein, hormones, hormone substitutes, and hormone antagonists, Signal Transduction, Adult, musculoskeletal diseases, medicine.medical_specialty, MESH: Cell Line, Tumor, Adolescent, MESH : Male, PTHrP, Blotting, Western, Ca++ signaling Pathways, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH: Cyclic AMP-Dependent Protein Kinases, Biology, MESH: Parathyroid Hormone-Related Protein, MESH: Prognosis, Adrenocortical Tumors, 03 medical and health sciences, Paracrine signalling, MESH : Receptor, Parathyroid Hormone, Type 1, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, Cell Line, Tumor, MESH : Adolescent, MESH : Cell Cycle, medicine, Didderential Expression, Humans, MESH: Blotting, Western, MESH : Middle Aged, RNA, Messenger, Autocrine, Autocrine signalling, Protein kinase A, MESH : Calcium, Protein kinase C, 030304 developmental biology, Aged, Receptor, Parathyroid Hormone, Type 1, MESH: RNA, Messenger, MESH : Signal Transduction, MESH: Adolescent, MESH: Humans, Parathyroid hormone-related protein, MESH : Cell Line, Tumor, MESH: Apoptosis, MESH : Humans, Parathyroid Hormone-Related Protein, Antagonist, MESH: Adult, Cyclic AMP-Dependent Protein Kinases, Adrenal Cortex Neoplasms, MESH: Male, Endocrinology, MESH: Receptor, Parathyroid Hormone, Type 1, Cancer research, Calcium, MESH: Female, MESH : Apoptosis
Abstract

Adrenocortical tumors (ACT) are rare and heterogeneous, but their pathogenesis is unclear. The oncoprotein parathyroid hormone–related protein (PTHrP), found in many common tumors, can regulate their growth in an autocrine/paracrine fashion through the PTH-R1 receptor. Little is known about the role of PTHrP in ACT. We monitored the synthesis of PTHrP and PTH-R1 in a series of 25 ACT: 12 adrenocortical carcinomas (ACC) and 13 adrenocortical adenomas (ACA), and investigated the effects of PTHrP(1-34) on H295R cells derived from an ACC. PTH-R1 mRNA and proteins were detected by real-time PCR and Western blotting in all the ACT samples and in H295R cells. Their concentrations did not differ significantly from one ACT to another. PTHrP mRNA was assayed by quantitative real-time PCR. It was detected in 90% of ACC, and in 10% of ACA. There was a positive correlation with the prognostic factors, McFarlane stage and Weiss score. Tissue-specific PTHrP protein processing was shown by Western blotting. Immunohistochemical staining revealed numerous, dense foci of PTHrP-containing cells in ACC, but few positive cells in ACA or normal tissue. PTHrP stimulated the growth of H295R cells, whereas a specific anti-PTHrP antibody and a PTHrP-R1 antagonist both enhanced their apoptosis. PTHrP activated both adenylate cyclase/protein kinase A and the intracellular calcium/protein kinase C pathways via PTHrP-R1. The active synthesis of PTHrP is linked to poor prognosis in ACC, in which it may act as an autocrine/paracrine factor in tumor growth and malignancy. (Cancer Epidemiol Biomarkers Prev 2008;17(9):2275–85)

Published
2008
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29. Methylation of specific CpG sites in the P2 promoter of parathyroid hormone-related protein determines the invasive potential of breast cancer cell lines.

Author

Tost J, Hamzaoui H, Busato F, Neyret A, Mourah S, Dupont JM, and Bouizar Z

Subjects
5' Flanking Region genetics, Azacitidine pharmacology, Cells, Cultured, CpG Islands drug effects, Epigenesis, Genetic, Female, Histones genetics, Humans, Hydroxamic Acids pharmacology, Neoplasm Invasiveness, Promoter Regions, Genetic drug effects, Breast Neoplasms pathology, CpG Islands genetics, DNA Methylation, Gene Expression Regulation, Neoplastic, Parathyroid Hormone-Related Protein genetics, Promoter Regions, Genetic genetics
Abstract

Parathyroid hormone-related protein (PTHrP) is upregulated in primary breast cancers and a major candidate for osteoclastic bone resorption present at sites of breast cancer to bone metastases. Using a human model of mammary epithelial cell lines differing in tumorigenicity and PTHrP expression, we investigated the role of epigenetic modifications for PTHrP expression. Quantitative analysis of the DNA methylation patterns at a total of 104 CpGs in the promoter region of PTHrP by pyrosequencing showed the absence of methylation in all analyzed cell lines in the large CpG island upstream of exon 1C. In the second intron of promoter 2 (P2) a region was identified containing 4 CpG nucleotides for which differential methylation correlated with the PTHrP expression level. The functional importance of this control mechanism was confirmed by the ability of the demethylating agent 5'-azacytidine to induce PTHrP mRNA and iPTHrP protein expression in previously non-expressing cell lines and increase their production by metastatic NS2T2A1 cells. In particular, transcription from P2 was activated non-tumoral S1T3 cells upon treatment with 5'-azacytidine. Our findings support the hypothesis that the methylation status of specific CpG dinucleotides is the dominant mechanism involved in silencing of PTHrP expression rather than the overall methylation of the CpG island. Methylation of the PTHrP P2 is a potential marker of breast cancer progression and might be used to evaluate the metastatic potential of breast tumors.

Published
2011
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30. Constitutive production of parathyroid hormone-related protein (PTHrP) by fibroblasts derived from normal and pathological human breast tissue.

Author

Cros M, Cataisson C, Cho YM, Berthois Y, Bernard-Poenaru O, Denne M, Graulet AM, De Vernejoul MC, Foley J, and Bouizar Z

Subjects
Antibodies pharmacology, Breast cytology, Breast metabolism, Cells, Cultured, Cyclic AMP metabolism, Cytokines metabolism, Endopeptidases metabolism, Enzyme Precursors metabolism, Female, Fibroblasts drug effects, Gene Expression, Humans, Immunohistochemistry methods, Matrix Metalloproteinase 1 metabolism, Matrix Metalloproteinase 2 metabolism, Parathyroid Hormone pharmacology, Parathyroid Hormone-Related Protein, Peptide Hormones genetics, Peptide Hormones pharmacology, Receptor, Parathyroid Hormone, Type 1, Receptors, Parathyroid Hormone genetics, Receptors, Parathyroid Hormone metabolism, Reference Values, Tumor Necrosis Factor-alpha immunology, Tumor Necrosis Factor-alpha metabolism, Breast Neoplasms metabolism, Breast Neoplasms pathology, Fibroblasts metabolism, Peptide Hormones metabolism
Abstract

Parathyroid hormone-related protein (PTHrP) is expressed in the mammary gland and appears to be critical to the morphogenesis of this structure. PTHrP production in the breast is generally attributed to epithelial cells. Because the stromal component of the breast produces factors implicated in proliferation and differentiation of mammary epithelial tissue and tumors, the aim of this study was to investigate the PTHrP expression by mammary fibroblasts from breast cancer tumors and normal breast. PTHrP antibodies labeled intralobular fibroblasts in normal breast and stromal fibroblasts that surround tumor cells. PTHrP was constitutively produced by the cultured mammary fibroblasts, independent of serum stimulation. Normal (15.83 +/- 1.72 fmol/10(6) cells) and pathological breast fibroblasts (19.87 +/- 5.76) secreted similar amounts of PTHrP. PTH/PTHrP receptor mRNA was detected by RT-PCR in all the samples tested. Fibroblasts from normal breast were both PTH and PTHrP-cAMP responsive (453 +/- 133% and 513 +/- 133%, respectively, from basal stimulation), whereas pathological breast fibroblasts were minimally PTHrP-cAMP responsive (183 +/- 36%). The production of other fibroblastic factors implicated in tumor growth and invasiveness was also examined. Interleukin-6 (IL-6), tumor necrosis factor-alpha (INF-alpha), and pro-matrix metalloproteinase (MMP)-1 were not affected by the status of the tissue. In contrast, increased levels of pro-MMP-2 were produced in fibroblasts that originated from pathological (290 +/- 62 ng/10(6) cells) samples compared with those from normal donors (125 +/- 41 ng/10(6) cells). PTHrP production was correlated with TNF-alpha and pro-MMP-2 production. However, inhibition with specific neutralizing antibodies against TNF-alpha or PTHrP, or with a PTHrP antagonist, showed that these factors did not regulate each other. In conclusion, breast fibroblasts are constitutive PTHrP-producing cells with the potential for autocrine signaling through the PTH/PTHrP receptor.

Published
2002

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