Defective expression of cellular retinol binding protein type I and retinoic acid receptors alpha2, beta2, and gamma2 in human breast cancer cells.
Because the retinoic acid (RA) signaling pathway regulates cell proliferation and differentiation, inactivation of genes integral to the pathway represents a potential mechanism of carcinogenesis. We have studied in human breast cancer cells (T47D, MCF-7, ZR75-1, MDA-MB-231, and BT20) the expression of a subset of retinoid signaling genes that are themselves transcriptionally up-regulated by RA, the cellular retinol binding protein type I (CRBPI) and the RA receptors (RARs) alpha2, beta2, and gamma2. We find that constitutive expression of these genes is low or undetectable, and that expression levels are seldom responsive to 24 h treatment with 1 microM all-trans or 9-cis RA (Northern blot analysis). This is in contrast to breast fibroblasts, which show RA-dependent expression of all four genes under the same conditions. Moreover, normal human breast epithelial cells express CRBPI and RARbeta2 at the mRNA level, suggesting that loss of expression of these genes is tied to malignant transformation. RARbeta2, but not CRBPI, was also expressed in RA-treated MTSV1-7 cells, an immortalized but nontumorigenic luminal epithelial cell line. Lack of CRBPI and RARbeta2 expression in cancer cells was not due to general impairment of RA signaling, as shown by RA activation of a RARE3-tk-CAT reporter in a subclone of MDA-MB-231 cells that did not express either CRBPI or RARbeta2. These results suggest that at least two independent defects in the expression of proteins that function in retinoid signaling may be involved in breast carcinogenesis.
Jing
Y
Y
Department of Medicine, Mount Sinai Medical Center, New York, New York 10029, USA.
Zhang
J
J
Bleiweiss
I J
IJ
Waxman
S
S
Zelent
A
A
Mira-Y-Lopez
R
R
D001943:Breast Neoplasms / Q000378:metabolism*; D002999:Clone Cells; D004848:Epithelium / Q000473:pathology; D005260:Female; D006801:Humans; D012333:RNA, Messenger / Q000032:analysis; D018168:Receptors, Retinoic Acid / Q000096:biosynthesis* / Q000235:genetics; D000072482:Retinoic Acid Receptor alpha; D012177:Retinol-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D054840:Retinol-Binding Proteins, Cellular; D014212:Tretinoin / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D000097768:Retinoic Acid Receptor gamma
D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D012177:Retinol-Binding Proteins; D054840:Retinol-Binding Proteins, Cellular; D014212:Tretinoin; D000097768:Retinoic Acid Receptor gamma; C000607071:RARA protein, human; C518456:RBP1 protein, human; C082925:retinoic acid receptor beta