Hypoxia and ERα Transcriptional Crosstalk Is Associated with Endocrine Resistance in Breast Cancer
Estrogen receptor-alpha (ERα) is the driving transcription factor in 70% of breast cancers and its activity is associated with hormone dependent tumor cell proliferation and survival. Given the recurrence of hormone resistant relapses, understanding the etiological factors fueling resistance is of m...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-10-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/14/19/4934 |
| _version_ | 1797480080314728448 |
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| author | Charly Jehanno Pascale Le Goff Denis Habauzit Yann Le Page Sylvain Lecomte Estelle Lecluze Frédéric Percevault Stéphane Avner Raphaël Métivier Denis Michel Gilles Flouriot |
| author_facet | Charly Jehanno Pascale Le Goff Denis Habauzit Yann Le Page Sylvain Lecomte Estelle Lecluze Frédéric Percevault Stéphane Avner Raphaël Métivier Denis Michel Gilles Flouriot |
| author_sort | Charly Jehanno |
| collection | DOAJ |
| description | Estrogen receptor-alpha (ERα) is the driving transcription factor in 70% of breast cancers and its activity is associated with hormone dependent tumor cell proliferation and survival. Given the recurrence of hormone resistant relapses, understanding the etiological factors fueling resistance is of major clinical interest. Hypoxia, a frequent feature of the solid tumor microenvironment, has been described to promote endocrine resistance by triggering ERα down-regulation in both in vitro and in vivo models. Yet, the consequences of hypoxia on ERα genomic activity remain largely elusive. In the present study, transcriptomic analysis shows that hypoxia regulates a fraction of ERα target genes, underlying an important regulatory overlap between hypoxic and estrogenic signaling. This gene expression reprogramming is associated with a massive reorganization of ERα cistrome, highlighted by a massive loss of ERα binding sites. Profiling of enhancer acetylation revealed a hormone independent enhancer activation at the vicinity of genes harboring hypoxia inducible factor (HIFα) binding sites, the major transcription factors governing hypoxic adaptation. This activation counterbalances the loss of ERα and sustains hormone-independent gene expression. We describe hypoxia in luminal ERα (+) breast cancer as a key factor interfering with endocrine therapies, associated with poor clinical prognosis in breast cancer patients. |
| first_indexed | 2024-03-09T21:55:57Z |
| format | Article |
| id | doaj.art-9e1cdc746dcf41ed979f8301d7d0158b |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-09T21:55:57Z |
| publishDate | 2022-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-9e1cdc746dcf41ed979f8301d7d0158b2023-11-23T19:59:08ZengMDPI AGCancers2072-66942022-10-011419493410.3390/cancers14194934Hypoxia and ERα Transcriptional Crosstalk Is Associated with Endocrine Resistance in Breast CancerCharly Jehanno0Pascale Le Goff1Denis Habauzit2Yann Le Page3Sylvain Lecomte4Estelle Lecluze5Frédéric Percevault6Stéphane Avner7Raphaël Métivier8Denis Michel9Gilles Flouriot10Inserm, EHESP, Irset (Institut de Recherche en Santé, Environnement et Travail)-UMR S1085, Rennes University, 35000 Rennes, FranceInserm, EHESP, Irset (Institut de Recherche en Santé, Environnement et Travail)-UMR S1085, Rennes University, 35000 Rennes, FranceInserm, EHESP, Irset (Institut de Recherche en Santé, Environnement et Travail)-UMR S1085, Rennes University, 35000 Rennes, FranceInserm, EHESP, Irset (Institut de Recherche en Santé, Environnement et Travail)-UMR S1085, Rennes University, 35000 Rennes, FranceInserm, EHESP, Irset (Institut de Recherche en Santé, Environnement et Travail)-UMR S1085, Rennes University, 35000 Rennes, FranceInserm, EHESP, Irset (Institut de Recherche en Santé, Environnement et Travail)-UMR S1085, Rennes University, 35000 Rennes, FranceInserm, EHESP, Irset (Institut de Recherche en Santé, Environnement et Travail)-UMR S1085, Rennes University, 35000 Rennes, FranceInstitut de Génétique et Développement de Rennes, UMR 6290 CNRS, Université de Rennes, 35000 Rennes, FranceInstitut de Génétique et Développement de Rennes, UMR 6290 CNRS, Université de Rennes, 35000 Rennes, FranceInserm, EHESP, Irset (Institut de Recherche en Santé, Environnement et Travail)-UMR S1085, Rennes University, 35000 Rennes, FranceInserm, EHESP, Irset (Institut de Recherche en Santé, Environnement et Travail)-UMR S1085, Rennes University, 35000 Rennes, FranceEstrogen receptor-alpha (ERα) is the driving transcription factor in 70% of breast cancers and its activity is associated with hormone dependent tumor cell proliferation and survival. Given the recurrence of hormone resistant relapses, understanding the etiological factors fueling resistance is of major clinical interest. Hypoxia, a frequent feature of the solid tumor microenvironment, has been described to promote endocrine resistance by triggering ERα down-regulation in both in vitro and in vivo models. Yet, the consequences of hypoxia on ERα genomic activity remain largely elusive. In the present study, transcriptomic analysis shows that hypoxia regulates a fraction of ERα target genes, underlying an important regulatory overlap between hypoxic and estrogenic signaling. This gene expression reprogramming is associated with a massive reorganization of ERα cistrome, highlighted by a massive loss of ERα binding sites. Profiling of enhancer acetylation revealed a hormone independent enhancer activation at the vicinity of genes harboring hypoxia inducible factor (HIFα) binding sites, the major transcription factors governing hypoxic adaptation. This activation counterbalances the loss of ERα and sustains hormone-independent gene expression. We describe hypoxia in luminal ERα (+) breast cancer as a key factor interfering with endocrine therapies, associated with poor clinical prognosis in breast cancer patients.https://www.mdpi.com/2072-6694/14/19/4934breast cancerestrogen receptor alphaendocrine resistancehypoxia |
| spellingShingle | Charly Jehanno Pascale Le Goff Denis Habauzit Yann Le Page Sylvain Lecomte Estelle Lecluze Frédéric Percevault Stéphane Avner Raphaël Métivier Denis Michel Gilles Flouriot Hypoxia and ERα Transcriptional Crosstalk Is Associated with Endocrine Resistance in Breast Cancer Cancers breast cancer estrogen receptor alpha endocrine resistance hypoxia |
| title | Hypoxia and ERα Transcriptional Crosstalk Is Associated with Endocrine Resistance in Breast Cancer |
| title_full | Hypoxia and ERα Transcriptional Crosstalk Is Associated with Endocrine Resistance in Breast Cancer |
| title_fullStr | Hypoxia and ERα Transcriptional Crosstalk Is Associated with Endocrine Resistance in Breast Cancer |
| title_full_unstemmed | Hypoxia and ERα Transcriptional Crosstalk Is Associated with Endocrine Resistance in Breast Cancer |
| title_short | Hypoxia and ERα Transcriptional Crosstalk Is Associated with Endocrine Resistance in Breast Cancer |
| title_sort | hypoxia and erα transcriptional crosstalk is associated with endocrine resistance in breast cancer |
| topic | breast cancer estrogen receptor alpha endocrine resistance hypoxia |
| url | https://www.mdpi.com/2072-6694/14/19/4934 |
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