Gene expression profiling reveals activation of the FA/BRCA pathway in advanced squamous cervical cancer with intrinsic resistance and therapy failure.
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.
The Oncology Institute "Prof Dr, Ion Chiricuta", 34-36 Republicii street, 400015 Cluj-Napoca, Romania. obalacescu@yahoo.com.
Ovidiu
O
Balacescu
Loredana
L
Balacescu
Oana
O
Tudoran
Nicolae
N
Todor
Meda
M
Rus
Rares
R
Buiga
Sergiu
S
Susman
Bogdan
B
Fetica
Laura
L
Pop
Laura
L
Maja
Simona
S
Visan
Claudia
C
Ordeanu
Ioana
I
Berindan-Neagoe
Viorica
V
Nagy
D000328:Adult; D000368:Aged; D019313:BRCA1 Protein / Q000096:biosynthesis*; D004268:DNA-Binding Proteins / Q000096:biosynthesis*; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000096:biosynthesis*; D051856:Fanconi Anemia Complementation Group Proteins; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D046228:Microarray Analysis; D008875:Middle Aged; D009367:Neoplasm Staging; D018307:Neoplasms, Squamous Cell / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D020365:RNA Helicases / Q000096:biosynthesis*; D051135:Rad51 Recombinase / Q000096:biosynthesis*; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology
D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D004268:DNA-Binding Proteins; C499905:FANCD2 protein, human; D052236:Fanconi Anemia Complementation Group D2 Protein; D051856:Fanconi Anemia Complementation Group Proteins; D051135:Rad51 Recombinase; C000618935:BRIP1 protein, human; D020365:RNA Helicases