Allelic loss of chromosome 3p24 correlates with tumor progression rather than with retinoic acid receptor β2 expression in breast carcinoma (original) (raw)
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Epigenetic downregulation of the retinoic acid receptor-beta2 gene in breast cancer
Journal of mammary gland biology and neoplasia, 2001
A growing body of evidence supports the hypothesis that the retinoic acid receptor beta2 (RAR-beta2) gene is a tumor suppressor gene which induces apoptosis and that the chemopreventive and therapeutic effects of retinoids are due to induction of RAR-beta2. During breast cancer progression, RAR-beta2 is reduced or even lost. It is known from studies of other tumor-suppressor genes that methylation of the 5'-region is the cause of loss of expression. Several groups demonstrated that this is also true for the RAR-beta2 in breast cancer by treating breast cancer cell lines with a demethylating agent and examining expression of the RAR-beta2 gene in response to a challenge with retinoic acid. Studies using sodium bisulfite genomic sequencing as well as methylation specific PCR showed that a number of breast cancer cell lines as well as breast cancer tissue showed signs of methylation. The RAR-beta2 gene was unmethylated in non-neoplastic breast tissue as well as in other normal tiss...
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.
Cancer Causes & Control, 2010
Epigenetic silencing of retinoic acid receptor-beta2 (RARbeta2) and estrogen receptor-alpha (ERalpha) expressions have been revealed to be important in the development of approaches for diagnosis and therapy of breast cancer. We aimed to explore the correlation of some potential factors with the hypermethylation status of RARbeta2 and ERalpha genes among Iranian breast cancer patients. The hypermethylation status was investigated in 137 dissected tissues from primary breast cancer patients through methylation-specific PCR. Overall, the methylation frequencies of RARbeta2 and ERalpha genes were observed in 36.5 and 51.1% of participants, respectively. The hypermethylated RARbeta2 was associated with younger age at diagnosis and negative family history of breast cancer. The hypermethylation of ERalpha was correlated positively with smoking, duration of estradiol exposure, ER-negativity in tumors and body mass index (at 5 years ago). The plasma levels of folate and vitamin B 12 were inversely related to the hypermethylation status of ERalpha, after controlling for covariates. The risk of ERalpha hypermethylation was increased with high plasma level of total homocysteine. In conclusion, our data provide new insights into the possible effect of some lifestylerelated factors on the aberrant methylation drift of ERalpha and RARbeta2 genes in breast cancer.
Genomic Antagonism between Retinoic Acid and Estrogen Signaling in Breast Cancer
Cell, 2009
Retinoic acid (RA) triggers antiproliferative effects in tumor cells, and therefore RA and its synthetic analogs have great potential as anticarcinogenic agents. Retinoic acid receptors (RARs) mediate RA effects by directly regulating gene expression. To define the genetic network regulated by RARs in breast cancer, we identified RAR genomic targets using chromatin immunoprecipitation and expression analysis. We found that RAR binding throughout the genome is highly coincident with estrogen receptor a (ERa) binding, resulting in a widespread crosstalk of RA and estrogen signaling to antagonistically regulate breast cancer-associated genes. ERa-and RARbinding sites appear to be coevolved on a large scale throughout the human genome, often resulting in competitive binding activity at nearby or overlapping cis-regulatory elements. The highly coordinated intersection between these two critical nuclear hormone receptor signaling pathways provides a global mechanism for balancing gene expression output via local regulatory interactions dispersed throughout the genome.
Cooperative interaction between retinoic acid receptor- and estrogen receptor in breast cancer
Genes & Development, 2010
Retinoic acid receptor-α (RARα) is a known estrogen target gene in breast cancer cells. The consequence of RARα induction by estrogen was previously unknown. We now show that RARα is required for efficient estrogen receptor-α (ER)-mediated transcription and cell proliferation. RARα can interact with ER-binding sites, but this occurs in an ER-dependent manner, providing a novel role for RARα that is independent of its classic role. We show, on a genome-wide scale, that RARα and ER can co-occupy regulatory regions together within the chromatin. This transcriptionally active co-occupancy and dependency occurs when exposed to the predominant breast cancer hormone, estrogen—an interaction that is promoted by the estrogen–ER induction of RARα. These findings implicate RARα as an essential component of the ER complex, potentially by maintaining ER–cofactor interactions, and suggest that different nuclear receptors can cooperate for effective transcriptional activity in breast cancer cells.
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
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.
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...
American journal of human genetics, 1990
Chromosome 13q has been suggested as the site of a gene predisposing to human breast cancer, because loss of heterozygosity of alleles on this chromosome has been observed in some ductal breast tumors and because two breast cancer lines are altered at the retinoblastoma gene (RB1) at 13q14. To test this possibility, linkage of breast cancer susceptibility to 14 loci on chromosome 13q loci was assessed in extended families in which breast cancer is apparently inherited as an autosomal dominant trait. RB1 was excluded as the site of a breast cancer gene by a lod score of Z = -7.60 at close linkage for 13 families. Multipoint analysis yielded negative lod scores throughout the region between 13q12 and 13q34; over most of this distance, Z less than -2.0. Therefore, chromosome 13q appears to be excluded as the site of primary lesion for breast cancer in these families. In addition, comparison of tumor versus normal tissues of nonfamilial breast cancer patients revealed an alteration at t...