Gene expression profiling reveals activation of the FA/BRCA pathway in advanced squamous cervical cancer with intrinsic resistance and therapy failure
| Autor: | Rares Buiga, Laura Pop, Claudia Ordeanu, Ovidiu Balacescu, Loredana Balacescu, Nicolae Todor, Oana Tudoran, Laura Iuliana Maja, Meda Rus, Bogdan Fetica, Ioana Berindan-Neagoe, Sergiu Susman, Viorica Nagy, Simona Visan |
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| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Adult
Cancer Research Microarray BRIP1 Uterine Cervical Neoplasms Treatment response Surgical oncology medicine Genetics Humans Neoplasms Squamous Cell Aged Neoplasm Staging Regulation of gene expression Cervical cancer Microarray analysis techniques business.industry BRCA1 Protein FANCD2 Fanconi Anemia Complementation Group D2 Protein Middle Aged medicine.disease BRCA1 Microarray Analysis Fanconi Anemia Complementation Group Proteins Gene expression profiling DNA-Binding Proteins Gene Expression Regulation Neoplastic Oncology Cancer research Immunohistochemistry RAD51 Female Rad51 Recombinase business RNA Helicases Research Article |
| Zdroj: | BMC Cancer |
| ISSN: | 1471-2407 |
| Popis: | Background Advanced squamous cervical cancer, one of the most commonly diagnosed cancers in women, still remains a major problem in oncology due to treatment failure and distant metastasis. Antitumor therapy failure is due to both intrinsic and acquired resistance; intrinsic resistance is often decisive for treatment response. In this study, we investigated the specific pathways and molecules responsible for baseline therapy failure in locally advanced squamous cervical cancer. Methods Twenty-one patients with locally advanced squamous cell carcinoma were enrolled in this study. Primary biopsies harvested prior to therapy were analyzed for whole human gene expression (Agilent) based on the patient’s 6 months clinical response. Ingenuity Pathway Analysis was used to investigate the altered molecular function and canonical pathways between the responding and non-responding patients. The microarray results were validated by qRT-PCR and immunohistochemistry. An additional set of 24 formalin-fixed paraffin-embedded cervical cancer samples was used for independent validation of the proteins of interest. Results A 2859-gene signature was identified to distinguish between responder and non-responder patients. ‘DNA Replication, Recombination and Repair’ represented one of the most important mechanisms activated in non-responsive cervical tumors, and the ‘Role of BRCA1 in DNA Damage Response’ was predicted to be the most significantly altered canonical pathway involved in intrinsic resistance (p = 1.86E-04, ratio = 0.262). Immunohistological staining confirmed increased expression of BRCA1, BRIP1, FANCD2 and RAD51 in non-responsive compared with responsive advanced squamous cervical cancer, both in the initial set of 21 cervical cancer samples and the second set of 24 samples. Conclusions Our findings suggest that FA/BRCA pathway plays an important role in treatment failure in advanced cervical cancer. The assessment of FANCD2, RAD51, BRCA1 and BRIP1 nuclear proteins could provide important information about the patients at risk for treatment failure. |
| Databáze: | OpenAIRE |
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