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Bone Factors Regulating the Osteotropism of Metastastic Breast Cancer

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Final rept. 22 Sep 1997-21 Sep 2000

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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 nunu 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.

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  • Anatomy and Physiology
  • Medicine and Medical Research

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