Estrogen Promotes Breast Cancer Cell Survival in an Inhibitor of Apoptosis (IAP)-dependent Manner
| Autor: | Adina Stanculescu, Kristina Borgen, Jonna Frasor, Elizabeth L. Wiley, Leslie A. Bembinster, Anna Bergamaschi |
|---|---|
| Rok vydání: | 2010 |
| Předmět: |
Oncology
Cancer Research Programmed cell death medicine.medical_specialty Cell Survival medicine.drug_class Ubiquitin-Protein Ligases Endocrinology Diabetes and Metabolism medicine.medical_treatment Blotting Western Estrogen receptor Breast Neoplasms Biology Inhibitor of apoptosis Polymerase Chain Reaction Article Inhibitor of Apoptosis Proteins Endocrinology Breast cancer Cell Line Tumor Internal medicine medicine Humans RNA Small Interfering Estradiol Tumor Necrosis Factor-alpha Endocrine and Autonomic Systems Carcinoma Ductal Breast Estrogens medicine.disease Immunohistochemistry Baculoviral IAP Repeat-Containing 3 Protein XIAP Gene Expression Regulation Neoplastic Cytokine Tissue Array Analysis Estrogen Cancer research Female Tumor necrosis factor alpha |
| Zdroj: | Hormones and Cancer. 1:127-135 |
| ISSN: | 1868-8500 1868-8497 |
| DOI: | 10.1007/s12672-010-0018-6 |
| Popis: | The estrogen receptor (ER) is a major prognostic and therapeutic marker that is expressed in nearly 75% of breast tumors. We have previously shown that the presence of inflammatory mediators can alter the genomic function of the estrogen receptor (ER) in a gene specific manner. In particular, 17β-estradiol (E2) works in combination with the pro-inflammatory cytokines to enhance the expression of a number of pro-survival factors, including the Inhibitor of Apoptosis (IAP) family member, cIAP2. Here we confirm that mRNA and protein levels for cIAP2, but not the related family members cIAP1 and XIAP, are highly up-regulated in MCF-7 breast cancer cells by E2 and cytokines. Similar regulation of cIAP2 is evident in other ER positive but not ER negative cell lines. In agreement with its role as a pro-survival factor, cIAP2 is highly expressed in a subset of invasive breast carcinomas but not in normal breast tissue or ductal carcinoma in situ. Antagonizing IAPs with mimetics of SMAC, which is a known endogenous IAP antagonist, or knockdown of IAPs by siRNA led to greater cell death by TNFα and prevented E2 from promoting cell survival. In addition, a SMAC mimetic reversed TNFα resistance in ER positive breast cancer cells that express high levels of endogenous IAPs. In summary, our findings indicate a new mechanism by which E2 allows breast cancer cells to evade cell death and suggest that an antagonist of IAPs may be a potential therapeutic option for a subset of ER positive breast tumors. |
| Databáze: | OpenAIRE |
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