Abstract
Background
Molecular segmentation of breast cancer allows identification of small groups of patients
who present high sensitivity to targeted agents. A patient, with chemo- and trastuzumab-resistant
HER2-overexpressing breast cancer, who presented concomitant acute promyelocytic leukemia,
showed a response in her breast lesions to retinoic acid, arsenic, and aracytin. We
therefore investigated whether RARA gene amplification could be associated with sensitivity to retinoic acid derivatives
in breast cancers.
Materials and Methods
Array comparative genomic hybridization and gene expression arrays were used to characterize
RARA amplifications and expression in 103 breast cancer samples. In vitro activity of
ATRA was characterized in T47D, SKBR3, and BT474 cell lines.
Results
Retinoic acid receptor alpha was gained or amplified in 27% of HER2-positive and 13%
of HER2-negative breast cancer samples. Retinoic acid receptor alpha can be coamplified
with HER2. Retinoic acid receptor alpha copy number changes could be correlated with messenger
RNA expression. All-trans-retinoic acid reduced cell viability of RARA-amplified, but not RARA-normal, cell lines through apoptosis. Gene expression arrays showed that ATRA-induced
apoptosis in RARA-amplified cell lines was related to an increase in CASP1 and IRF1.
Conclusion
The results of this study suggest that breast cancers exhibiting RARA amplifications could be sensitive to retinoic acid. A phase II trial will evaluate
this hypothesis in the clinical setting.
Keywords
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References
- Biology-driven phase II trials: what is the optimal model for molecular selection?.J Clin Oncol. 2011; 29: 1236-1238
- Human breast cancer:correlation of relapse and survival with amplification of the HER2/neu oncogene.Science. 1987; 235: 177-182
- Phase II study of weekly intravenous recombinant humanized anti-p185HER2 monoclonal antibody in patients with HER2/neu-overexpressing metastatic breast cancer.J Clin Oncol. 1996; 14: 737-744
- Molecular predictors of response to trastuzumab and lapatinib in breast cancer.Nat Rev Clin Oncol. 2010; 7: 98-107
- How retinoids regulate breast cancer cell proliferation and apoptosis.Cell Mol Life Sci. 2004; 61: 1475-1484
- Anti-tumor effects of retinoids combined with trastuzumab or tamoxifen in breast cancer cells: induction of apoptosis by retinoid/trastuzumab combinations.Breast Cancer Res. 2010; 12 (R62)
- Hypomethylation and induction of retinoic acid receptor beta 2 by concurrent action of adenosine analogues and natural compounds in breast cancer cells.Eur J Pharmacol. 2010; 638: 47-53
- Pharmacokinetics and clinical impact of all-trans retinoic acid in metastatic breast cancer: a phase II trial.Cancer Chemother Pharmacol. 1997; 40: 335-341
- A pilot phase II trial of all-trans retinoic acid (Vesanoid) and paclitaxel (Taxol) in patients with recurrent or metastatic breast cancer.Invest New Drugs. 2011; 29: 1482-1487
- Very high frequency of hypermethylated genes in breast cancer metastasis to the bone, brain, and lung.Clin Cancer Res. 2004; 10: 3104-3109
- Randomized phase II trial of all-trans-retinoic acid with chemotherapy based on paclitaxel and cisplatin as first-line treatment in patients with advanced non-small-cell lung cancer.J Clin Oncol. 2010; 28: 3463-3471
- Synergistic antitumor activity of lapatinib and retinoids on a novel subtype of breast cancer with coamplification of ERBB2 and RARA.Oncogene. 2012; 31: 3431-3443
- Molecular characterization of breast cancer with high-resolution oligonucleotide comparative genomic hybridization array.Clin Cancer Res. 2009; 15: 441-451
- A high-resolution integrated analysis of genetic and expression profiles of breast cancer cell lines.Breast Cancer Res Treat. 2009; 118: 481-498
- Genomic analysis of the HER2/TOP2A amplicon in breast cancer and breast cancer cell lines.Lab Invest. 2008; 88: 491-503
- Linear models and empirical bayes methods for assessing differential expression in microarray experiments.Stat Appl Genet Mol Biol. 2004; 3 (Article 3)
- An IRF1-dependent pathway of DNA damage-induced apoptosis in mitogen-activated T lymphocytes.Nature. 1995; 376: 596-599
- Interferon-regulatory factor-1 is critical for tamoxifen-mediated apoptosis in human mammary epithelial cells.Oncogene. 2004; 23: 8743-8755
- The promise of retinoids to fight against cancer.Nat Rev Cancer. 2001; 1: 181-193
- Chemoprevention: an essential approach to controlling cancer.Nat Rev Cancer. 2002; 2: 537-543
- Amplification of the RARA gene in acute myeloid leukemia: significant finding or coincidental observation?.Cancer Genet Cytogenet. 2010; 202: 33-37
- Does chromosome 17 centromere copy number predict polysomy in breast cancer? A fluorescence in situ hybridization and microarray-based CGH analysis.J Pathol. 2009; 219: 16-24
- Retinoid-resistant estrogen receptor-negative human breast carcinoma cells transfected with retinoic acid receptor-alpha acquire sensitivity to growth inhibition by retinoids.J Biol Chem. 1994; 269: 21440-21447
- Regulation of IRF and STAT gene expression by retinoic acid.Leuk Lymphoma. 1998; 30: 63-71
Article info
Publication history
Published online: July 08, 2013
Accepted:
February 4,
2013
Received in revised form:
December 28,
2012
Received:
June 26,
2012
Footnotes
Samar Alsafadi and Caroline Even contributed equally to this work and should be considered joint first authors.
Identification
Copyright
© 2013 Elsevier Inc. Published by Elsevier Inc. All rights reserved.
