Background: Advanced squamous cervical cancer, one of the most commonly diagnosed cancers in women, still\nremains a major problem in oncology due to treatment failure and distant metastasis. Antitumor therapy failure is\ndue to both intrinsic and acquired resistance; intrinsic resistance is often decisive for treatment response. In this\nstudy, we investigated the specific pathways and molecules responsible for baseline therapy failure in locally\nadvanced squamous cervical cancer.\nMethods: Twenty-one patients with locally advanced squamous cell carcinoma were enrolled in this study. Primary\nbiopsies harvested prior to therapy were analyzed for whole human gene [removed]Agilent) based on the\npatientââ?¬â?¢s 6 months clinical response. Ingenuity Pathway Analysis was used to investigate the altered molecular\nfunction and canonical pathways between the responding and non-responding patients. The microarray results\nwere validated by qRT-PCR and immunohistochemistry. An additional set of 24 formalin-fixed paraffin-embedded\ncervical cancer samples was used for independent validation of the proteins of interest.\nResults: A 2859-gene signature was identified to distinguish between responder and non-responder patients.\nââ?¬Ë?DNA Replication, Recombination and Repairââ?¬â?¢ represented one of the most important mechanisms activated in\nnon-responsive cervical tumors, and the ââ?¬Ë?Role of BRCA1 in DNA Damage Responseââ?¬â?¢ was predicted to be the most\nsignificantly altered canonical pathway involved in intrinsic resistance (p = 1.86E-04, ratio = 0.262). Immunohistological\nstaining confirmed increased expression of BRCA1, BRIP1, FANCD2 and RAD51 in non-responsive compared with\nresponsive advanced squamous cervical cancer, both in the initial set of 21 cervical cancer samples and the second set\nof 24 samples.\nConclusions: Our findings suggest that FA/BRCA pathway plays an important role in treatment failure in advanced\ncervical cancer. The assessment of FANCD2, RAD51, BRCA1 and BRIP1 nuclear proteins could provide important\ninformation about the patients at risk for treatment failure.
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