Bone Factors Regulating the Osteotropism of Metastastic Breast Cancer
Abstract
Malignant breast adenocarcinoma cells mimic osteoblasts, a critical step in their metastatic colonization and destruction of bone. CBFAl, a transcription factor responsible for normal osteoblast differentiation, is expressed inappropriately by the human breast adenocarcinoma cell line MDA-MB-23 1, and about 2-fold more strongly by a subline Ml, recovered from an osteolytic bone metastasis of MDA-MB-23 1 in a nu/nu mouse. CBFAl expression was not detected in normal breast epithelium (HMEC cells). Experiments involved semiquantitative RT-PCR and SD S-PAGE immunoblot analyis of nuclear lysates with a specific CBFAl antibody. Electrophoretic mobility shift with labeled oligonucleotide containing the binding site for CBFAl demonstrated fUNctional CBFAl protein in nuclear extracts of MB-MDA-23 1 cells but not HMEC. CBFAl expression by adenocarcinoma may explain anomalous expression of "Osteoblast-specific" genes (mimicry), because these genes typically have CBFAl response elements in their 5%-promoters; osteocalcin is a prime example. Ostecalcin expression was analyzed in human breast adenocarcinoma MCF-7 (detectable human osteocalcin), MB-MDA-23 1 (low levels), and normal breast HMEC (no osteocalcin). Co-culture of MCF-7 with a normal mouse osteoblast line (MC3T3-El) increased human osteocalcin expression by the tumor cells. This effect could be reproduced by addition 0 conditioned medium from proliferating MC3T3-El. Thus, CBFAl expression appears to provide breast adenocarcinoma cells with an advantage in the bone microenvironment% and may explain their observed mimicry of certain aspects of the normal osteoblast. Microarray survey of gene expression patterns in osteoblasts and adenocarcinoma cells in co-culture revealed that the proximity 0 tumor and bone cells in a skeletal metastasis may allow paracrine effects to suppress osteogenic repair while enhancing tumor survival and osteolysis.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2000
- Accession Number
- ADB264621
Entities
People
- Peter V. Hauschka