Gene expression profiling reveals activation of the FA/BRCA pathway in advanced squamous cervical cancer with intrinsic resistance and therapy failure

BMC Cancer

Viorica Nagy¹  Ioana Berindan-Neagoe¹  Claudia Ordeanu³  Simona Visan²  Laura Maja³  Laura Pop¹  Bogdan Fetica³  Sergiu Susman¹  Rares Buiga³  Meda Rus³  Nicolae Todor³  Oana Tudoran³  Loredana Balacescu³  Ovidiu Balacescu³ 

[1]Iuliu Hatieganu, University of Medicine and Pharmacy, 8 Babes street, 400012 Cluj-Napoca, Romania

[2]Faculty of Veterinary Medicine, University of Agricultural Sciences and Veterinary Medicine, 3-5 Calea Manastur street, 400372 Cluj-Napoca, Romania

[3]The Oncology Institute "Prof Dr. Ion Chiricuta", 34-36 Republicii street, 400015 Cluj-Napoca, Romania

关键词: Treatment response;    Microarray;    Cervical cancer;    BRIP1;    BRCA1;    RAD51;    FANCD2;   

Others  :  858911
DOI  :  10.1186/1471-2407-14-246

 received in 2013-08-12, accepted in 2014-04-03,  发布年份 2014

【 摘 要 】

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.

【 授权许可】

   
2014 Balacescu et al.; licensee BioMed Central Ltd.

【 图 表 】

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