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Enhanced IFNα Signaling Promotes Ligand-Independent Activation of ERα to Promote Aromatase Inhibitor Resistance in Breast Cancer
Enhanced IFNα Signaling Promotes Ligand-Independent Activation of ERα to Promote Aromatase Inhibitor Resistance in Breast Cancer
- Source :
- Cancers, Cancers, Vol 13, Iss 5130, p 5130 (2021), Cancers; Volume 13; Issue 20; Pages: 5130
- Publication Year :
- 2021
- Publisher :
- MDPI AG, 2021.
-
Abstract
- Simple Summary Interferon alpha (IFNα) signaling is highly upregulated in ER+ breast cancers that become resistant to estrogen deprivation therapy. This study uncovers how enhanced (IFNα)/JAK-STAT signaling directly influences estrogen receptor (ERα) activation in the absence of estrogen. We found that inhibiting IFNα signaling downregulates expression and activation of ERα. In addition, STAT1 and ERα directly interact and regulate a key interferon-stimulated gene, IFITM1, in AI-resistant breast cancer cells. We demonstrate that crosstalk occurs between IFNα and ERα pathways, which contributes to aggression and survival of AI-resistant breast cancer, thus representing a novel mechanism of acquired AI resistance. Abstract Aromatase inhibitors (AIs) reduce estrogen levels up to 98% as the standard practice to treat postmenopausal women with estrogen receptor-positive (ER+) breast cancer. However, approximately 30% of ER+ breast cancers develop resistance to treatment. Enhanced interferon-alpha (IFNα) signaling is upregulated in breast cancers resistant to AIs, which drives expression of a key regulator of survival, interferon-induced transmembrane protein 1 (IFITM1). However, how upregulated IFNα signaling mediates AI resistance is unknown. In this study, we utilized MCF-7:5C cells, a breast cancer cell model of AI resistance, and demonstrate that these cells exhibit enhanced IFNα signaling and ligand-independent activation of the estrogen receptor (ERα). Experiments demonstrated that STAT1, the mediator of intracellular signaling for IFNα, can interact directly with ERα. Notably, inhibition of IFNα signaling significantly reduced ERα protein expression and ER-regulated genes. In addition, loss of ERα suppressed IFITM1 expression, which was associated with cell death. Notably, chromatin immunoprecipitation experiments validated that both ERα and STAT1 associate with ERE sequences in the IFITM1 promoter. Overall, hyperactivation of IFNα signaling enhances ligand-independent activation of ERα, which promotes ER-regulated, and interferon stimulated gene expression to promote survival in AI-resistant breast cancer cells.
- Subjects :
- Cancer Research
medicine.drug_class
breast cancer
aromatase inhibitor
estrogen deprivation
AI resistance
estrogen receptor
interferon alpha
interferon-stimulated genes
IFITM1
STAT1
Estrogen receptor
Article
Downregulation and upregulation
medicine
Aromatase
RC254-282
Aromatase inhibitor
biology
Chemistry
Interferon-stimulated gene
Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Oncology
Estrogen
Cancer research
biology.protein
Chromatin immunoprecipitation
Subjects
Details
- ISSN :
- 20726694
- Volume :
- 13
- Database :
- OpenAIRE
- Journal :
- Cancers
- Accession number :
- edsair.doi.dedup.....6015ee3f81d44e89a59939687ae5950e
- Full Text :
- https://doi.org/10.3390/cancers13205130