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Systems Biology of Metabolic Regulation by Estrogen Receptor Signaling in Breast Cancer
Published on: March 17, 2016
Comparative gene expression profiling reveals partially overlapping but distinct genomic actions of different
Claudio Scafoglio1, Concetta Ambrosino, Luigi Cicatiello
1Dipartimento di Patologia generale, Seconda Università degli Studi di Napoli, Vico L. De Crecchio 7, 80138 Naples, Italy.
Abstract:
Antiestrogens used for breast cancer (BC) treatment differ among each other for the ability to affect estrogen receptor (ER) activity and thereby inhibit hormone-responsive cell functions and viability. We used high-density cDNA microarrays for a comprehensive definition of the gene pathways affected by 17beta-estradiol (E2), ICI 182,780 (ICI), 4OH-tamoxifen (Tamoxifen), and raloxifene (RAL) in ER-positive ZR-75.1 cells, a suitable model to investigate estrogen and antiestrogen actions in hormone-responsive BC. The expression of 601 genes was significantly affected by E2 in these cells; in silico analysis reveals that 86 among them include one or more potential ER binding site within or near the promoter and that the binding site signatures for E2F-1, NF-Y, and NRF-1 transcription factors are significantly enriched in the promoters of genes induced by estrogen treatment, while those for CAC-binding protein and LF-A1 in those repressed by the hormone, pointing to novel transcriptional effectors of secondary responses to estrogen in BC cells. Interestingly, expression of 176 E2-regulated mRNAs was unaffected by any of the antiestrogens tested, despite the fact that under the same conditions the transcriptional and cell cycle stimulatory activities of ER were inhibited. On the other hand, of 373 antiestrogen-responsive genes identified here, 52 were unresponsive to estrogen and 25% responded specifically to only one of the compounds tested, revealing non-overlapping and clearly distinguishable effects of the different antiestrogens in BC cells. As some of these differences reflect specificities of the mechanism of action of the antiestrogens tested, we propose to exploit this gene set for characterization of novel hormonal antagonists and selective estrogen receptor modulators (SERMs) and as a tool for testing new associations of antiestrogens, more effective against BC.
Insights
Different antiestrogens show distinct effects on gene expression in breast cancer (BC) cells, offering new avenues for targeted therapies. This research identifies specific gene sets modulated by antiestrogens, aiding in the development of novel hormonal antagonists and selective estrogen receptor modulators (SERMs).
Area of Science:
- Molecular Biology
- Genomics
- Endocrinology
Background:
- Antiestrogens are crucial in breast cancer (BC) treatment, but their varying effects on estrogen receptor (ER) activity require detailed investigation.
- Understanding the specific gene pathways influenced by different antiestrogens is key to optimizing BC therapy and developing novel agents.
Purpose of the Study:
- To comprehensively define gene pathways affected by 17beta-estradiol (E2) and various antiestrogens (ICI 182,780, 4OH-tamoxifen, raloxifene) in ER-positive BC cells.
- To identify novel transcriptional effectors of estrogen responses and to characterize the distinct gene expression profiles induced by different antiestrogens.
Main Methods:
- Utilized high-density cDNA microarrays to analyze gene expression changes in ZR-75.1 cells treated with E2, ICI 182,780, tamoxifen, and raloxifene.
- Performed in silico analysis to identify potential ER binding sites and enriched transcription factor binding signatures in E2-regulated genes.
- Compared gene expression profiles to distinguish between E2-regulated, antiestrogen-unresponsive, and specifically antiestrogen-responsive genes.
Main Results:
- E2 significantly affected 601 genes; in silico analysis identified potential ER binding sites and enriched transcription factor signatures (E2F-1, NF-Y, NRF-1) in induced genes.
- 176 E2-regulated mRNAs were unaffected by antiestrogens, despite ER activity inhibition, indicating complex regulatory mechanisms.
- 373 antiestrogen-responsive genes were identified, with 52 being estrogen-unresponsive and 25% responding to only one compound, highlighting distinct antiestrogen effects.
Conclusions:
- Different antiestrogens exhibit non-overlapping and distinguishable effects on gene expression in BC cells, reflecting specific mechanisms of action.
- The identified gene sets can serve as a tool for characterizing novel hormonal antagonists and selective estrogen receptor modulators (SERMs).
- This research provides a foundation for developing more effective BC therapies by testing new combinations of antiestrogens.
