title: Regulation of parathyroid hormone-related peptide by estradiol: effect on tumor growth and metastasis in vitro and in vivo.
abstract: We evaluated the capacity of estradiol (E(2)) to regulate PTHrP production, cell growth, tumor growth, and metastasis to the skeleton in breast cancer. In estrogen receptor (ER)-negative human breast cancer cells, MDA-MB-231, and cells transfected with full-length cDNA encoding ER (S-30), E(2) caused a marked decrease in cell growth and PTHrP production, effects that were abrogated by anti-E(2) tamoxifen. E(2) also inhibited PTHrP promoter activity in S-30 cells. For in vivo studies, MDA-MB-231 and S-30 cells were inoculated into the mammary fat pad of female BALB/c nu.nu mice. Animals receiving S-30 cells developed tumors of significantly smaller volume compared with MDA-MB-231 tumor-bearing animals. This change in tumor volume was reversed when S-30 cells were inoculated into ovariectomized (OVX) hosts. Inoculation of MDA-MB-231 cells into the left ventricle resulted in the development of lesions in femora and tibia as determined by x-ray analysis. In contrast, these lesions were significantly smaller in volume and number in animals inoculated with S-30, and this lower incidence was reversed in OVX animals. Bone histological analysis showed that the tumor volume to tissue volume ratio was comparable with that seen by x-ray. Immunohistochemical analysis showed that PTHrP production was inhibited in S-30 group and restored to levels comparable to that seen in MDA-MB-231 tumor-bearing animals when S-30 cells were inoculated in OVX animals. Collectively these studies show that E(2) production is inversely correlated with PTHrP production and that the growth-promoting effect of PTHrP has a direct impact on tumor growth at both nonskeletal and skeletal sites.
authors.affiliation: Department of Medicine and Oncology, McGill University Health Centre, Montreal, Quebec, Canada H3A 1A1. shafaat.rabbani@mcgill.ca
authors.forename: S A
authors.initials: SA
authors.lastname: Rabbani
authors.forename: P
authors.initials: P
authors.lastname: Khalili
authors.forename: A
authors.initials: A
authors.lastname: Arakelian
authors.forename: H
authors.initials: H
authors.lastname: Pizzi
authors.forename: G
authors.initials: G
authors.lastname: Chen
authors.forename: D
authors.initials: D
authors.lastname: Goltzman
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000000981:diagnostic imaging / Q000473:pathology / Q000556:secondary*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000556:secondary*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D004958:Estradiol / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism; D005260:Female; D020868:Gene Silencing; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D010052:Ovariectomy; D044162:Parathyroid Hormone-Related Protein / Q000096:biosynthesis*; D011859:Radiography; D014162:Transfection; D014183:Transplantation, Heterologous
chemical_list: D047628:Estrogen Receptor alpha; D044162:Parathyroid Hormone-Related Protein; D004958:Estradiol