PubMed · 2034743
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L Munick. 1991. Cremation after augmentation.. https://doi.org/10.1097/00006534-199106000-00037
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The expression of retinoic acid receptor-beta (RAR beta) mRNA is absent or down-regulated in a majority of breast cancers, suggesting that loss of retinoic acid receptor function may be a critical event in breast cancer carcinogenesis. We developed an in vitro system to investigate whether the loss of retinoic acid receptor (RAR) function might affect the proliferation and structural differentiation of normal cultured human mammary epithelial cells (HMECs). Utilizing a truncated retinoic acid receptor (RAR)-alpha construct exhibiting dominant-negative activity against retinoic acid receptor isoforms alpha, beta, and gamma (DNRAR), we inhibited normal retinoic acid receptor function in HMECs. Suppression of RAR function in HMECs resulted in reduced growth inhibition mediated by all-trans-retinoic acid (ATRA). Moreover, the doubling time of HMECs expressing the DNRAR was significantly shortened, associated with a decrease in the percentage of cells in G1 and an increase in the percentage of cells in S-phase relative to controls. In addition, HMECs expressing the DNRAR cultured in prepared extracellular matrix exhibited a loss of extracellular matrix-induced growth arrest and formation of a polarized ductal epthelium. Our results suggest that ATRA and RARs may play an important role in regulating the proliferation of HMECs and in promoting differentiation.
nm23 gene expression is strictly related to the state of cell growth. The level of its expression parallels the fraction of thymidine-incorporating cells (S-phase cells) in neoplastic mammary tissues and in the synchronously cycling fraction of MCF 1OA cells. nm23.h1 reaches a peak of expression in the S-phase, and is present at very low level during the GO/G1 phase. Two strategies are used to demonstrate the direct involvement of the nm23.h1 gene in the process of cell proliferation. The first consists of transient inhibition of nm23.h1 expression by using anti-sense oligonucleotide treatment; weak inhibitory effect on cell proliferation is observed. The second strategy involves the stable inhibition of nm23.h1 expression by transfection of MCF1OA cells with a plasmid vector expressing the human nm23.h1 anti-sense mRNA. The anti-sense-transfected cells show consistently slower proliferative activity than the control.
Alterations of the entire long arm of chromosome 1 are the most consistent cytogenetic abnormalities found in human breast carcinoma. Overexpression of a large number of genes, because of acquisition of additional copies of one arm or a whole chromosome, is one possible cause of the imbalance in cell metabolism. To investigate the existence of such a gene dosage effect in breast cancer, we chose to study the MUC1 mucin gene located at 1q21-q24. This gene is highly expressed in breast tumors, but the genetic mechanism for its ectopic overexpression is not clearly known. Thirty-two human primary breast tumors were examined, by Southern blot DNA and northern blot RNA analyses, for allelic dosage and expression of the MUC1 gene. A correlation was found between acquisition of additional copies of MUC1 gene and high mRNA levels (p < 0.0001). These results identify a genetic mechanism responsible for MUC1 gene overexpression and support the hypothesis that a gene dosage effect of the long arm of chromosome 1 may be involved in the pathogenesis of breast cancer.