Regulation of parathyroid hormone-related peptide by estradiol: effect on tumor growth and metastasis in vitro and in vivo.
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.
Rabbani
S A
SA
Department of Medicine and Oncology, McGill University Health Centre, Montreal, Quebec, Canada H3A 1A1. shafaat.rabbani@mcgill.ca
Khalili
P
P
Arakelian
A
A
Pizzi
H
H
Chen
G
G
Goltzman
D
D
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
D047628:Estrogen Receptor alpha; D044162:Parathyroid Hormone-Related Protein; D004958:Estradiol