Loss of Retinoic Acid Receptor fi Expression in Breast Cancer and Morphologically Normal Adjacent Tissue but not in the Normal Breast Tissue Distant from the Cancer1 (original) (raw)
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Breast Cancer Research and Treatment, 2001
A tumor suppressor gene, retinoic acid receptor (RAR) β2, has been mapped to chromosome 3p24, a region where loss of heterozygosity (LOH) has been observed commonly in carcinomas of various tumor tissues. RAR β2 expression is reduced or lost in many malignant tumors including breast cancer, however, whether LOH accounts for the loss of expression of RAR β2 in breast cancer is unknown. We, therefore, assessed LOH on chromosome band 3p24 to correlate it with RAR β2 expression and other established prognostic parameters in 52 breast carcinomas. Based on three microsatellites, D3S 1283, D3S 1293 and D3S 1286, all of the tumors were informative, of these, 12 (23%) exhibited LOH. RAR β2 expression was lost in 42% (19/45) of these samples. We found that LOH on chromosome band 3p24 was not correlated with loss of RAR β2, but correlated with higher histological grade, p53-positivity, and loss of estrogen and progesterone receptors. Our findings suggest that LOH of the RAR β2 gene does not account for the frequent loss of RAR β2 expression in breast cancer but the genomic structural alteration at or close to the RAR β2 gene locus are likely to be associated with tumor progression and/or loss of hormonal dependency.
European Journal of Endocrinology, 1997
Retinoids seem to act as agents of chemoprevention and differentiation in breast diseases. Their action is mediated by nuclear receptors, retinoic acid receptors (RARa, RARb, RARg) and retinoid X receptors (RXRa, RXRb, RXRg) and modulated by cellular retinol binding proteins (CRBP). There are few published data on CRBP expression. In this study, we evaluated the expression of RARa, b and g and CRBP type I (CRBP-I) gene expression in fibrocystic disease (FD) and in breast cancer (BC), studying 14 FD and 20 BC surgical samples by reverse transcription (RT)-PCR. We also evaluated mRNA concentrations in cancer samples by a semiquantitative PCR method, co-amplifying RARa, RARb and CRBP-I genes with an unrelated gene, glyceraldehyde 3-phosphate dehydrogenase (GAPDH), as internal control. All benign and malignant breast tissues expressed RARa, b and g, and CRBP-I mRNAs. A greater concentration of RARb mRNA was detected in cancer tissues with lower oestrogen and progesterone receptor concentrations, whereas RARa was detected in variable concentrations that were not related to those of steroid receptors. The CRBP-I concentration was similar in all samples studied. We demonstrated that all three RARs and CRBP-I transcripts are expressed in FD, and that RARb, RARg and CRBP-I mRNAs also are present in BC tissues. This indicates that both malignant and benign breast tissues may be target for retinoids, justifying the use of natural and synthetic vitamin A derivatives in the chemoprevention of breast disease.
Cancer Science, 2000
Smoking prevention will decrease lung cancer incidence in time. However, early detection would improve lung cancer prognosis in subjects at risk provided that specific markers could be identified. We previously reported that retinoic acid receptor (RAR) and retinoid X receptor (RXR) expression was altered in lung tumors. RAR- gene status could be derived from corresponding allelotyping and immunohistochemistry data. We now report the continued study on lung cancer precursor lesions. Fluorescence PCR-based assays were used for allelotyping at the RAR/ RXR loci of: (a) 66 lung precursor lesions found at the free resection margins of 41 patients undergoing surgery for lung cancer (؉ 31 paired tumors); and (b) bronchial cells also found at the free resection margins from 16 current and 8 never smokers operated on for noncancerous diseases. Three microsatellites located at 3p14 -21 and 9p21 were also used for interwork comparison. Immunohistochemistry was additionally performed to evaluate P53 and RAR- expression in precursor lesions. 2 tests showed significant differences (P < 0.05) when comparing the results obtained from never smokers, smokers, squamous metaplasia, dysplasia ؉ in situ carcinoma, and tumors. Microsatellite changes occurred frequently in all samples, but without specificity for any group (P < 0.08 -0.52). They were globally correlated with tobacco exposure (P < 0.04), for which the RAR-␥ marker appeared as a preferential target (P < 0.004). Few reparation error phenotypes were observed, mostly at the RXR-␣ and RXR-␥ markers for which combined changes were also linearly increasing from never smokers to dysplasia ؉ in situ carcinoma (P < 0.05 and P < 0.03). RAR- marker losses also increased from the first to the last group studied (P < 0.01), with a concomitant decrease in RAR- protein expression and correlated p53 increased immunoreactivity (P < 0.02). Losses at 3p14, 3p21, and P16 were frequent, but no significant differences between groups could be found. Unexpectedly, high constitutive homozygosity was observed near the RAR-␣ locus in squamous cell lung cancer cases. RARs/RXRs form homodimers or heterodimers involved in ligand binding. Their added alterations could result in a state of functional vitamin A deficiency in the affected bronchial cells. Further deletion events drawn from a limited repertoire of specific regions such as 3p14 -21 and 9p21 could subsequently drive the deficient cells to invasive carcinoma.
Cancer Research, 2004
Retinoids regulate gene transcription through activating retinoic acid receptors (RARs)/retinoic X receptors (RXRs). Of the three RAR receptors (␣, , and ␥), RAR has been considered a tumor suppressor gene. Here, we identified a novel RAR isoform-RAR5 in breast epithelial cells, which could play a negative role in RAR signaling. Similar to RAR2, the first exon (59 bp) of RAR5 is RAR5 isoform specific, whereas the other exons are common to all of the RAR isoforms. The first exon of RAR5 does not contain any translation start codon, and therefore its protein translation begins at an internal methionine codon of RAR2, lacking the A, B, and part of C domain of RAR2. RAR5 protein was preferentially expressed in estrogen receptor-negative breast cancer cells and normal breast epithelial cells that are relatively resistant to retinoids, whereas estrogen receptor-positive cells that did not express detectable RAR5 protein were sensitive to retinoid treatment, suggesting that this isoform may affect the cellular response to retinoids. RAR5 isoform is unique among all of the RARs, because a corresponding isoform was not detectable for either RAR␣ or RAR␥. RAR5 mRNA was variably expressed in normal and cancerous breast epithelial cells. Its transcription was under the control of a distinct promoter P3, which can be activated by all-trans-retinoic acid (atRA) and other RAR/RXR selective retinoids in MCF-7 and T47D breast cancer cells. We mapped the RAR5 promoter and found a region -302/-99 to be the target region of atRA. In conclusion, we identified and initially characterized RAR5 in normal, premalignant, and malignant breast epithelial cells. RAR5 may serve as a potential target of retinoids in prevention and therapy studies.
type I and retinoic acid receptors a2, 32, and y2 in human breast cancer cells
2000
Because the retinoic acid (RA) signal- ing pathway regulates cell proliferation and differen- tiation, 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 BT2O) the ex- pression of a subset of retinoid signaling genes that are themselves transcriptionally up-regulated by HA, the cellular
EMBO molecular medicine, 2015
Forty-two cell lines recapitulating mammary carcinoma heterogeneity were profiled for all-trans retinoic acid (ATRA) sensitivity. Luminal and ER(+) (estrogen-receptor-positive) cell lines are generally sensitive to ATRA, while refractoriness/low sensitivity is associated with a Basal phenotype and HER2 positivity. Indeed, only 2 Basal cell lines (MDA-MB157 and HCC-1599) are highly sensitive to the retinoid. Sensitivity of HCC-1599 cells is confirmed in xenotransplanted mice. Short-term tissue-slice cultures of surgical samples validate the cell-line results and support the concept that a high proportion of Luminal/ER(+) carcinomas are ATRA sensitive, while triple-negative (Basal) and HER2-positive tumors tend to be retinoid resistant. Pathway-oriented analysis of the constitutive gene-expression profiles in the cell lines identifies RARα as the member of the retinoid pathway directly associated with a Luminal phenotype, estrogen positivity and ATRA sensitivity. RARα3 is the major tr...
Breast Cancer Research and Treatment, 1999
To elucidate the role of RAR-dependent gene transcription in inhibiting breast cell growth, we have investigated the ability of retinoids to suppress growth of normal, immortal, and malignant breast cells. We compared the ability of all trans retinoic acid (atRA) to activate retinoid receptors in normal, immortal, and malignant breast cells, with its ability to inhibit the growth of these cells. Our studies demonstrate that normal breast cells are more sensitive to the growth inhibitory effect of atRA than are immortal nonmalignant breast cells and breast cancer cells. atRA activated RAR-dependent gene transcription in both atRA-sensitive and-resistant breast cells as determined by transfection of a RARE-containing reporter gene. These results demonstrate that activation of RAR-dependent gene transcription by atRA is not sufficient to inhibit growth in atRA-resistant breast cancer cells. To determine whether activation of RAR-dependent gene transcription by atRA is necessary for growth inhibition, we tested the growth suppressive effect of a retinoid (BMS453) which binds RAR receptors and transrepresses AP-1 but does not activate RAR-dependent gene expression. This retinoid inhibited the growth of normal breast cells (HMEC and 184) and T47D breast cancer cells. Breast cancer cells which were resistant to atRA, were also resistant to BMS453. Normal human breast cells were most sensitive to the anti-proliferative effects of BMS453. These results indicate that in some breast cells RAR-dependent transactivation is not necessary for retinoids to inhibit growth. Instead, retinoids may suppress growth by inhibiting transcription factors such as AP-1 through transcription factor crosstalk.
Cancer Research, 2006
Biological effects of retinoids are mediated via retinoic acid (RA) receptors (RAR) and retinoid X receptors (RXR). The best-characterized mechanism of retinoid action is stimulation of transcription from promoters containing RA response elements (RARE). Retinoids induce senescence-like growth arrest in MCF-7 breast carcinoma cells; this effect is associated with the induction of several growth-inhibitory genes. We have now found that these genes are induced by RAR-specific but not by RXR-specific ligands. Genome-scale microarray analysis of gene expression was used to compare the effects of two pan-RAR ligands, one of which is a strong agonist of RARE-dependent transcription, whereas the other induces such transcription only weakly and antagonizes the inducing effect of RAR agonists. Both RAR ligands, however, produced very similar effects on gene expression in MCF-7 cells, suggesting that RARE-dependent transcription is only a minor component of retinoid-induced changes in gene expression. The effects of RAR ligands on gene expression parallel changes associated with damage-induced senescence, and both ligands induced G 1 arrest and the senescent phenotype in MCF-7 cells. The RAR ligands up-regulated many tumor-suppressive genes and down-regulated multiple genes with oncogenic activities. Genes that are strongly induced by RAR ligands encode secreted bioactive proteins, including several tumor-suppressing factors. In agreement with these observations, retinoid-treated MCF-7 cells inhibited the growth of retinoid-insensitive MDA-MB-231 breast carcinoma cells in coculture. These results indicate that RARE-independent transcriptional effects of RAR ligands lead to senescence-like growth arrest and paracrine growthinhibitory activity in MCF-7 breast carcinoma cells.