Identification of prospective factors promoting osteotropism in breast cancer: a potential role for CITED2.
Breast cancer metastases develop in the bone more frequently than any other site and are a common cause of morbidity in the form of bone pain, pathological fractures, nerve compression and life-threatening hypercalcemia. Despite ongoing research efforts, the molecular and cellular mechanisms that regulate breast cancer cell homing to and colonization of the bone as well as resultant pathological bone alteration remain poorly understood. To identify key mediators promoting breast cancer metastasis to bone, we utilized an immunocompetent, syngeneic murine model of breast cancer metastasis employing the mammary tumor cell line NT2.5. Following intracardiac injection of NT2.5 cells in neu-N mice, metastases developed in the bone, liver and lung, closely mimicking the anatomical distribution of metastases in patients with breast cancer. Using an in vivo selection process, we established NT2.5 sublines demonstrating an enhanced ability to colonize the bone and liver. Genome-wide cDNA microarray analysis comparing gene expression between parental NT2.5 cells and established sublines revealed both known and novel mediators of bone metastasis and osteolysis, including the transcriptional co-activator CITED2. In further studies, we found that expression of CITED2 was elevated in human primary breast tumors and bone metastasis compared to normal mammary epithelium and was highest in breast cancer cell lines that cause osteolytic bone metastasis in animal models. In addition, reducing CITED2 expression in NT2.5 cells inhibited the establishment of bone metastasis and osteolysis in vivo, suggesting a potential role for CITED2 in promoting breast cancer bone metastasis.
Lau
Wen Min
WM
Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Weber
Kristy L
KL
Doucet
Michele
M
Chou
Yu-Ting
YT
Brady
Kelly
K
Kowalski
Jeanne
J
Tsai
Hua-Ling
HL
Yang
Justin
J
Kominsky
Scott L
SL
D000818:Animals; D001859:Bone Neoplasms / Q000473:pathology* / Q000556:secondary; D001943:Breast Neoplasms / Q000473:pathology*; D002448:Cell Adhesion / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D045744:Cell Line, Tumor; D004273:DNA, Neoplasm / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000473:pathology / Q000556:secondary; D051379:Mice; D009362:Neoplasm Metastasis / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D010014:Osteolysis / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics* / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D015534:Trans-Activators / Q000235:genetics* / Q000502:physiology; D014158:Transcription, Genetic
C486381:CITED2 protein, human; D004273:DNA, Neoplasm; D012333:RNA, Messenger; D012097:Repressor Proteins; D015534:Trans-Activators