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Submitted on January 14, 2005
Accepted on April 4, 2005
Department of Medicine and Oncology, McGill University Health Center, Montreal, QC, Canada
* To whom correspondence should be addressed. E-mail: shafaat.rabbani{at}mcgill.ca.
We evaluated the capacity of estradiol (E2) to regulate parathyroid hormone related protein (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), E2 caused a marked decrease in cell growth and PTHrP production; effects which were abrogated by anti-E2 tamoxifen (TAM). E2 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 
. 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/tissue volume ratio (TuV/TV) 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 E2 production is inversely correlated with PTHrP production and that the growth promoting effect of PTHrP has a direct impact on tumor growth at both non-skeletal and skeletal sites.
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