Abstract
Simple SummaryInterferon 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.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.
Highlights
Introduction distributed under the terms andBreast cancer is the most frequently diagnosed cancer among women in the UnitedStates (U.S.) and the second highest cause of death
We discovered that Aromatase inhibitors (AIs)-resistant MCF-7:5C breast cancer cells constitutively express enhanced ERα expression as well as ER-regulated genes compared to AI-sensitive MCF-7 and T47D cells and that blockade of IFNα signaling or knockdown of STAT1/2 markedly reduces ERα expression and ERregulated genes in these cells
We found that AI-resistant MCF-7:5C cells expressed markedly elevated levels of total and phosphorylated (S167 and S118) ERα compared to MCF-7 and T47D cells and that ERα was primarily localized in the nucleus in MCF-7:5C cells, indicating a constitutively activated state (Figure 1A,B)
Summary
Introduction distributed under the terms andBreast cancer is the most frequently diagnosed cancer among women in the UnitedStates (U.S.) and the second highest cause of death. Breast cancer is the most frequently diagnosed cancer among women in the United. It is estimated that in 2021, approximately 281,550 U.S women will receive a diagnosis of invasive breast cancer and. 43,000 women will die from the disease [1,2,3,4]. The most frequently diagnosed subtype of conditions of the Creative Commons. Breast cancer is ER+ (estrogen receptor and/or progesterone receptor positive) accounting for approximately 70% of diagnoses [5,6]. Because estrogen promotes cancer progression, the standard treatment for ER+ breast cancer blocks ERα signaling. Aromatase inhibitors (AIs), which decrease estrogen production by 90–98%, are the standard of care for postmenopausal ER+ breast cancer [7,8,9,10]. Despite the efficacy of AIs, approximately 30%
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