title: Vitamin D deficiency promotes growth of MCF-7 human breast cancer in a rodent model of osteosclerotic bone metastasis.
abstract: BACKGROUND
  Breast cancer metastases to bone are common in advanced stage disease. We have recently demonstrated that vitamin D deficiency enhances breast cancer growth in an osteolytic mouse model of breast cancer metastasis. In this study, we examined the effects of vitamin D deficiency on tumor growth in an osteosclerotic model of intra-skeletal breast cancer in mice.
  
  
  METHODS
  The effects of 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] on proliferation and apoptosis of MCF-7 breast cancer cells, and changes in the expression of genes within the vitamin D metabolic pathway (VDR, 1α- and 24-hydroxylase) were examined in vitro. MCF-7 breast cancer cells were injected intra-tibially into vitamin D deficient and vitamin D sufficient mice co-treated with and without osteoprotegerin (OPG). The development of tumor-related lesions was monitored via serial X-ray analysis. Tumor burden and indices of proliferation and apoptosis were determined by histology along with markers of bone turnover and serum intact PTH levels.
  
  
  RESULTS
  In vitro, MCF-7 cells expressed critical genes for vitamin D signalling and metabolism. Treatment with 1,25(OH)(2)D(3) inhibited cell growth and proliferation, and increased apoptosis. In vivo, osteosclerotic lesions developed faster and were larger at endpoint in the tibiae of vitamin D deficient mice compared to vitamin D sufficient mice (1.49±0.08 mm(2) versus 1.68±0.15 mm(2), P<0.05). Tumor area was increased by 55.8% in vitamin D deficient mice (0.81±0.13 mm(2) versus 0.52±0.11 mm(2) in vitamin D sufficient mice). OPG treatment inhibited bone turnover and caused an increase in PTH levels, while tumor burden was reduced by 90.4% in vitamin D sufficient mice and by 92.6% in vitamin D deficient mice. Tumor mitotic activity was increased in the tibiae of vitamin D deficient mice and apoptosis was decreased, consistent with faster growth.
  
  
  CONCLUSIONS
  Vitamin D deficiency enhances both the growth of tumors and the tumor-induced osteosclerotic changes in the tibiae of mice following intratibial implantation of MCF-7 cells. Enhancement of tumor growth appears dependent on increased bone resorption rather than increased bone formation induced by these tumors.
authors.affiliation: Bone Research Program, ANZAC Research Institute, University of Sydney, Australia.
authors.forename: Li Laine
authors.initials: LL
authors.lastname: Ooi
authors.forename: Yu
authors.initials: Y
authors.lastname: Zheng
authors.forename: Hong
authors.initials: H
authors.lastname: Zhou
authors.forename: Trupti
authors.initials: T
authors.lastname: Trivedi
authors.forename: Arthur D
authors.initials: AD
authors.lastname: Conigrave
authors.forename: Markus J
authors.initials: MJ
authors.lastname: Seibel
authors.forename: Colin R
authors.initials: CR
authors.lastname: Dunstan
mesh_terms: D000135:Acid Phosphatase / Q000378:metabolism; D000273:Adipose Tissue / Q000187:drug effects / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001859:Bone Neoplasms / Q000150:complications* / Q000000981:diagnostic imaging / Q000503:physiopathology / Q000556:secondary*; D016723:Bone Remodeling / Q000187:drug effects; D001842:Bone and Bones / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology*; D002117:Calcitriol / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D051379:Mice; D010014:Osteolysis / Q000150:complications / Q000473:pathology; D010026:Osteosclerosis / Q000150:complications* / Q000201:enzymology / Q000473:pathology; D011859:Radiography; D000071681:Tartrate-Resistant Acid Phosphatase; D047368:Tumor Burden / Q000187:drug effects; D014808:Vitamin D Deficiency / Q000150:complications* / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D007527:Isoenzymes; D000135:Acid Phosphatase; D000071681:Tartrate-Resistant Acid Phosphatase; D002117:Calcitriol