Interferon-Stimulated Genes Are Transcriptionally Repressed by PR in Breast Cancer

Walter, K.; Goodman, Merit L.; Singhal, Hari; Hall, Jade A.; Li, Tianbao; Holloran, Sean M.; Trinca, Gloria M.; Gibson, Katelin A.; Jin, Victor X.; Greene, Geoffrey L.; Hagan, Christy R.

doi:10.1158/1541-7786.mcr-17-0180

Cited by 31 publications

(40 citation statements)

References 50 publications

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“…Furthermore, an increasing percentage of MX2 IHC negative samples was observed in metastatic lesions. The exact mechanism of this downregulation needs further elucidation, but inactivation of the IFN pathway and suppression of its target genes during disease development has been reported in melanoma as well as in other cancers (Katlinskaya et al, ; Katlinski et al, ; Walter et al, ). Interestingly, a study of breast cancer by Han et al (Han, Russo, Kohwi, & Kohwi‐Shigematsu, ) found that transcription factor and chromatin organizer SATB1 reprograms gene expression profile of cancer cells to promote tumor growth and that MX2 is among the repressed genes.…”

Section: Discussionmentioning

confidence: 99%

MX 2 is a novel regulator of cell cycle in melanoma cells

Juraleviciute

Poźniak

Nsengimana

et al. 2019

Pigment Cell Melanoma Res

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MX2 protein is a dynamin‐like GTPase2 that has recently been identified as an interferon‐induced restriction factor of HIV‐1 and other primate lentiviruses. A single nucleotide polymorphism (SNP), rs45430, in an intron of the MX2 gene, was previously reported as a novel melanoma susceptibility locus in genome‐wide association studies. Functionally, however, it is still unclear whether and how MX2 contributes to melanoma susceptibility and tumorigenesis. Here, we show that MX2 is differentially expressed in melanoma tumors and cell lines, with most metastatic cell lines showing lower MX2 expression than primary melanoma cell lines and melanocytes. Furthermore, high expression of MX2 RNA in primary melanoma tumors is associated with better patient survival. Overexpression of MX2 reduces in vivo proliferation partially through inhibition of AKT activation, suggesting that it can act as a tumor suppressor in melanoma. However, we have also identified a subset of melanoma cell lines with high endogenous MX2 expression where downregulation of MX2 leads to reduced proliferation. In these cells, MX2 downregulation interfered with DNA replication and cell cycle processes. Collectively, our data for the first time show that MX2 is functionally involved in the regulation of melanoma proliferation but that its function is context‐dependent.

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Section: Discussionmentioning

confidence: 99%

MX 2 is a novel regulator of cell cycle in melanoma cells

Juraleviciute

Poźniak

Nsengimana

et al. 2019

Pigment Cell Melanoma Res

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“…Western blot analysis was performed as previously described. 15,16 Primary antibodies for immunoblotting are as follows: PR (sc-7208; Santa Cruz Biotechnology), phospho-STAT2 (4441; Cell Signaling), Total STAT2 (sc-1668; Santa Cruz Biotechnology), IFIT3 (sc-393512; Santa Cruz Biotechnology), IFIT1 (14769; Cell Signaling), STAT1 (9172; Cell Signaling), Ubiquitin (3933; Cell Signaling), and betatubulin (2128; Cell Signaling). Densitometry to quantify immunoblots was performed using ImageJ.…”

Section: Western Blot Analysismentioning

confidence: 99%

“…Our previous studies have concluded that PR can inhibit type I interferon signaling at multiple steps along the cascade, including prevention of STAT1 phosphorylation, DNA binding, and ISG transcription. 15,16 Because of the biological importance of interferon signaling (prevention of infection and disease spread), compensatory mechanisms have been discovered in the absence of a functional STAT1 complex. In some instances, STAT2 is able to propagate the interferon response without STAT1, thus suggesting that multiple antagonistic mechanisms are necessary to fully hinder interferon signaling.…”

Section: Introductionmentioning

confidence: 99%

Progesterone receptor promotes degradation of STAT2 to inhibit the interferon response in breast cancer

2020

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Type I (IFNα/β) interferon signaling represents a critical transduction pathway involved in recognition and destruction of nascent tumor cells. Downregulation of this pathway to promote a more immunosuppressed microenvironment contributes to the ability of tumor cells to evade the immune system, a known Hallmark of Cancer. The present study investigates the progesterone receptor (PR), which is expressed in the vast majority of breast cancers, and its ability to inhibit efficient interferon signaling in tumor cells. We have shown that PR can block the interferon signaling cascade by promoting ubiquitination and degradation of STAT2. Targeting STAT2 is critical, as we show that it is an essential protein in inducing transcription of interferon-stimulated genes (ISG); shRNA-mediated knockdown of STAT2 severely abrogates the interferon response in vitro. Importantly, we were able to reverse this inhibition by treating with onapristone, an anti-progestin currently being investigated in breast cancer clinical trials. Additionally, we have found that an interferon-related gene signature (composed of ISGs) is inversely correlated with PR expression in human tumors. We speculate that PR inhibition of interferon signaling may contribute to creating an immunosuppressed microenvironment and reversal of this through anti-progestins may present a novel therapeutic target to promote immune activity within the tumor.

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“…RNA was amplified using MessageAmpII aRNA amplification kit (Life Technologies) and reverse transcribed to cDNA using SMARTScribe Reverse Transcriptase (Clontech Laboratories, Inc.) and random nonamer primers. Real-time quantitative PCR (qPCR) was performed for selected estrogen and progesterone response genes and others of interest using hydrolysis probes as previously described (31,36). Baseline and postintervention specimens were assessed together.…”

Section: Gene Expression By Rt-qpcrmentioning

confidence: 99%

Effect of Bazedoxifene and Conjugated Estrogen (Duavee) on Breast Cancer Risk Biomarkers in High-Risk Women: A Pilot Study

Fabian

Nye

Powers

et al. 2019

Cancer Prevention Research

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Interventions that relieve vasomotor symptoms while reducing risk for breast cancer would likely improve uptake of chemoprevention for perimenopausal and postmenopausal women. We conducted a pilot study with 6 months of the tissue selective estrogen complex bazedoxifene (20 mg) and conjugated estrogen (0.45 mg; Duavee) to assess feasibility and effects on risk biomarkers for postmenopausal breast cancer. Risk biomarkers included fully automated mammographic volumetric density (Volpara), benign breast tissue Ki-67 (MIB-1 immunochemistry), and serum levels of progesterone, IGF-1, and IGFBP3, bioavailable estradiol and testosterone. Twenty-eight perimenopausal and postmenopausal women at increased risk for breast cancer were enrolled: 13 in cohort A with baseline Ki-67 < 1% and 15 in cohort B with baseline Ki-67 of 1% to 4%. All completed the study with > 85% drug adherence. Significant changes in biomarkers, uncorrected for multiple comparisons, were a decrease in mammographic fibroglandular volume (P ¼ 0.043); decreases in serum progesterone, bioavailable testosterone, and IGF-1 (P < 0.01), an increase in serum bioavailable estradiol (P < 0.001), and for women from cohort B a reduction in Ki-67 (P ¼ 0.017). An improvement in median hot flash score from 15 at baseline to 0 at 6 months, and menopause-specific quality-of-life total, vasomotor, and sexual domain scores were also observed (P < 0.001). Given the favorable effects on risk biomarkers and patient reported outcomes, a placebocontrolled phase IIB trial is warranted.

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Interferon-Stimulated Genes Are Transcriptionally Repressed by PR in Breast Cancer

Cited by 31 publications

References 50 publications

MX 2 is a novel regulator of cell cycle in melanoma cells

MX 2 is a novel regulator of cell cycle in melanoma cells

Progesterone receptor promotes degradation of STAT2 to inhibit the interferon response in breast cancer

Effect of Bazedoxifene and Conjugated Estrogen (Duavee) on Breast Cancer Risk Biomarkers in High-Risk Women: A Pilot Study

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