scholarly journals The Role of Interferon Regulatory Factor-1 (IRF1) in Overcoming Antiestrogen Resistance in the Treatment of Breast Cancer

2011 ◽  
Vol 2011 ◽  
pp. 1-9 ◽  
Author(s):  
J. L. Schwartz ◽  
A. N. Shajahan ◽  
R. Clarke
Keyword(s):  
Breast Cancer ◽  
Endocrine Therapy ◽  
Cell Fate ◽  
Interferon Regulatory Factor ◽  
Breast Cancers ◽  
Breast Cancer Patients ◽  
Regulatory Factor ◽  
Inhibition Of Proliferation ◽  
P53 Expression ◽  
Interferon Regulatory Factor 1

Resistance to endocrine therapy is common among breast cancer patients with estrogen receptor alpha-positive (ER+) tumors and limits the success of this therapeutic strategy. While the mechanisms that regulate endocrine responsiveness and cell fate are not fully understood, interferon regulatory factor-1 (IRF1) is strongly implicated as a key regulatory node in the underlying signaling network. IRF1 is a tumor suppressor that mediates cell fate by facilitating apoptosis and can do so with or without functional p53. Expression of IRF1 is downregulated in endocrine-resistant breast cancer cells, protecting these cells from IRF1-induced inhibition of proliferation and/or induction of cell death. Nonetheless, when IRF1 expression is induced following IFNγtreatment, antiestrogen sensitivity is restored by a process that includes the inhibition of prosurvival BCL2 family members and caspase activation. These data suggest that a combination of endocrine therapy and compounds that effectively induce IRF1 expression may be useful for the treatment of many ER+ breast cancers. By understanding IRF1 signaling in the context of endocrine responsiveness, we may be able to develop novel therapeutic strategies and better predict how patients will respond to endocrine therapy.

scholarly journals Interferon Regulatory Factor-1 Signaling Regulates the Switch between Autophagy and Apoptosis to Determine Breast Cancer Cell Fate

2015 ◽  
Vol 75 (6) ◽  
pp. 1046-1055 ◽  
Author(s):  
Jessica L. Schwartz-Roberts ◽  
Katherine L. Cook ◽  
Chun Chen ◽  
Ayesha N. Shajahan-Haq ◽  
Margaret Axelrod ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Fate ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Interferon Regulatory Factor ◽  
Regulatory Factor ◽  
Interferon Regulatory Factor 1

p53 and bcl-2 expression correlates with clinical outcome in a series of node-positive breast cancer patients.

1996 ◽  
Vol 14 (5) ◽  
pp. 1604-1610 ◽  
Author(s):  
R Silvestrini ◽  
E Benini ◽  
S Veneroni ◽  
M G Daidone ◽  
G Tomasic ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clinical Outcome ◽  
Mitochondrial Protein ◽  
Axillary Node ◽  
Breast Cancers ◽  
Breast Cancer Patients ◽  
Prognostic Information ◽  
P53 Overexpression ◽  
P53 Expression ◽  
Node Positive

BACKGROUND AND PURPOSE The tumor-suppressor gene TP53 and the proto-oncogene bcl-2 encode, respectively, for a nuclear phosphoprotein and for a mitochondrial protein involved in multiple cellular functions. The proteins provide prognostic information in node-negative breast cancer and are supposed to influence treatment responsiveness. We analyzed the predictive role of p53 and bcl-2 expression, alone and in association with other variables, in postmenopausal women with node-positive, estrogen receptor-positive (ER+) breast cancers treated with radical or conservative surgery plus radiotherapy and adjuvant tamoxifen for at least 1 year. PATIENTS AND METHODS On 240 resectable cancers, we determined the expression of p53 and bcl-2, using immunohistochemistry, cell proliferation (3H-thymidine labeling index [3H-dT LI]), and ER and progesterone receptors (PgR). RESULTS p53 expression and 3H-dT LI were weakly related to one another and both were unrelated to bcl-2. Relapse-free and distant metastasis-free survival at 5 years were significantly lower for patients with tumors that highly expressed p53 (P = .0001) and for those that weakly expressed or did not express bcl-2 (P = .02). However, p53, but not bcl-2, provided prognostic information independent of tumor size, axillary node involvement, steroid receptors, and 3H-dT LI. Moreover, the simultaneous p53 overexpression and lack of PgR identified patients at maximum risk of relapse, whereas bcl-2 overexpression, associated with a low 3H-dT LI or the presence of PgR, improved the prognostic resolution for low-risk patients. CONCLUSION p53 expression appears to be indicative of clinical outcome in postmenopausal patients treated with tamoxifen. Whether p53 overexpression and weak bcl-2 expression are indicators of biologic aggressiveness, regardless of treatment, or of hormone resistance remains to be defined.

The A4396G polymorphism in interferon regulatory factor 1 is frequently expressed in breast cancer cell lines

2007 ◽  
Vol 175 (1) ◽  
pp. 61-64 ◽  
Author(s):  
Kerrie B. Bouker ◽  
Todd C. Skaar ◽  
David S. Harburger ◽  
Rebecca B. Riggins ◽  
David R. Fernandez ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Cancer Cell Lines ◽  
Interferon Regulatory Factor ◽  
Breast Cancer Cell Lines ◽  
Regulatory Factor ◽  
Interferon Regulatory Factor 1

scholarly journals Level of Combined Estrogen and Progesterone Receptor Expression Determines the Eligibility for Adjuvant Endocrine Therapy in Breast Cancer Patients

Cancers ◽  
2021 ◽  
Vol 13 (19) ◽  
pp. 5007
Author(s):  
Jee Hyun Ahn ◽  
Soon Bo Choi ◽  
Jung Min Park ◽  
Jee Ye Kim ◽  
Hyung Seok Park ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Progesterone Receptor ◽  
Endocrine Therapy ◽  
Adjuvant Endocrine Therapy ◽  
Receptor Expression ◽  
Breast Cancers ◽  
Breast Cancer Patients ◽  
Limited Data ◽  
Single Receptor

Hormone receptor (HR)-positive breast cancer has a heterogeneous pattern according to the level of receptor expression. Patients whose breast cancers express low levels of estrogen receptor (ER) or progesterone receptor (PgR) may be eligible for adjuvant endocrine therapy, but limited data are available to support this notion. We aimed to determine whether HR expression level is related to prognosis. Tumors from 6042 patients with breast cancer were retrospectively analyzed for combined HR levels of ER and PgR. Low expression was defined as ER 1–10% and PgR 1–20%. Four HR groups were identified by combining ER and PgR expression levels. Patients whose tumors expressed high levels of a single receptor showed the worst survival outcomes, and their risk continuously increased even after the 10-year follow-up. Endocrine therapy had a significant benefit for patients whose tumors expressed high HR levels and a favorable tendency for patients with tumors expressing low HR levels. We established the possible benefit of endocrine therapy for patients whose breast tumors expressed low HR levels. Thus, HR level was a prognostic factor and might be a determinant of extended therapy, especially for patients with high expression of a single receptor.

scholarly journals Interferon Regulatory Factor 1 (IRF-1) and IRF-2 Expression in Breast Cancer Tissue Microarrays

2005 ◽  
Vol 25 (10) ◽  
pp. 587-594 ◽  
Author(s):  
Judith M. Connett ◽  
Linda Badri ◽  
Thomas J. Giordano ◽  
William C. Connett ◽  
Gerard M. Doherty
Keyword(s):  
Breast Cancer ◽  
Tissue Microarrays ◽  
Interferon Regulatory Factor ◽  
Breast Cancer Tissue ◽  
Cancer Tissue ◽  
Regulatory Factor ◽  
Interferon Regulatory Factor 1

scholarly journals The proapoptotic gene interferon regulatory factor-1 mediates the antiproliferative outcome of paired box 2 gene and tamoxifen

Oncogene ◽  
2020 ◽  
Vol 39 (40) ◽  
pp. 6300-6312
Author(s):  
Shixiong Wang ◽  
Venkata S. Somisetty ◽  
Baoyan Bai ◽  
Igor Chernukhin ◽  
Henri Niskanen ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Growth ◽  
Interferon Regulatory Factor ◽  
Estrogen Signaling ◽  
Tamoxifen Treatment ◽  
Dependent Manner ◽  
Breast Cancer Patients ◽  
Regulatory Factor ◽  
Interferon Regulatory Factor 1 ◽  
Er Positive

Abstract Tamoxifen is the most prescribed selective estrogen receptor (ER) modulator in patients with ER-positive breast cancers. Tamoxifen requires the transcription factor paired box 2 protein (PAX2) to repress the transcription of ERBB2/HER2. Now, we identified that PAX2 inhibits cell growth of ER+/HER2− tumor cells in a dose-dependent manner. Moreover, we have identified that cell growth inhibition can be achieved by expressing moderate levels of PAX2 in combination with tamoxifen treatment. Global run-on sequencing of cells overexpressing PAX2, when coupled with PAX2 ChIP-seq, identified common targets regulated by both PAX2 and tamoxifen. The data revealed that PAX2 can inhibit estrogen-induced gene transcription and this effect is enhanced by tamoxifen, suggesting that they converge on repression of the same targets. Moreover, PAX2 and tamoxifen have an additive effect and both induce coding genes and enhancer RNAs (eRNAs). PAX2–tamoxifen upregulated genes are also enriched with PAX2 eRNAs. The enrichment of eRNAs is associated with the highest expression of genes that positivity regulate apoptotic processes. In luminal tumors, the expression of a subset of these proapoptotic genes predicts good outcome and their expression are significantly reduced in tumors of patients with relapse to tamoxifen treatment. Mechanistically, PAX2 and tamoxifen coexert an antitumoral effect by maintaining high levels of transcription of tumor suppressors that promote cell death. The apoptotic effect is mediated in large part by the gene interferon regulatory factor 1. Altogether, we conclude that PAX2 contributes to better clinical outcome in tamoxifen treated ER-positive breast cancer patients by repressing estrogen signaling and inducing cell death related pathways.

scholarly journals FASN Inhibition as a Potential Treatment for Endocrine-Resistant Breast Cancer

2021 ◽  
Author(s):  
Aleksandra Gruslova ◽  
Bryan McClellan ◽  
Henriette Balinda ◽  
Suryavathi Viswanadhapalli ◽  
Victoria Alers ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Subcellular Localization ◽  
Endocrine Therapy ◽  
Fatty Acid Synthase ◽  
Tumor Grade ◽  
Resistant Cell ◽  
Breast Cancers ◽  
Inhibition Of Proliferation ◽  
Tamoxifen Resistant ◽  
Resistant Cells

Abstract PurposeThe majority of breast cancers are estrogen receptor (ERα) positive making endocrine therapy a mainstay for these patients. Unfortunately, resistance to endocrine therapy is a common occurrence. Fatty acid synthase (FASN) is a key enzyme in lipid biosynthesis and its expression is commensurate with tumor grade and resistance to numerous therapies. MethodsThe effect of the FASN inhibitor TVB-3166 on ERα expression and cell growth was characterized in tamoxifen resistant cell lines, xenografts, and patient explants. Subcellular localization of ERα was assessed using a combination of immunofluorescence and subcellular fractionations. Palmitoylation and ubiquitination of ERα were assessed by immunoprecipitation. ERα and p-eIF2α protein levels were analyzed by western blotting after treatment with TVB-3166 with or without the addition of palmitate or BAPTA. ResultsTVB-3166 treatment leads to a marked inhibition of proliferation in tamoxifen-resistant cells compared to the parental cells. Additionally, TVB-3166 significantly inhibited tamoxifen-resistant breast tumor growth in mice and decreased proliferation of primary tumor explants compared to untreated controls. FASN inhibition significantly reduced ERα levels most prominently in endocrine resistant cells and altered its subcellular localization. Furthermore, we showed that the reduction of ERα expression upon TVB-3166 treatment is mediated through the induction of endoplasmic reticulum stress. ConclusionOur preclinical data provide evidence that FASN inhibition by TVB-3166 presents a promising therapeutic strategy for treatment of endocrine-resistant breast cancer. Further clinical development of FASN inhibitors for endocrine resistant breast cancer should be considered.

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