Gene expression profile of residual breast cancer after doxorubicin and cyclophosphamide neoadjuvant chemotherapy.
In breast cancer patients, primary chemotherapy is associated with the same survival benefits as adjuvant chemotherapy. Residual tumors represent a clinical challenge, as they may be resistant to additional cycles of the same drugs. Our aim was to identify differential transcripts expressed in residual tumors, after neoadjuvant chemotherapy, that might be related with tumor resistance. Hence, 16 patients with paired tumor samples, collected before and after treatment (4 cycles doxorubicin/cyclophosphamide, AC) had their gene expression evaluated on cDNA microarray slides containing 4,608 genes. Three hundred and eighty-nine genes were differentially expressed (paired Student's t-test, pFDR<0.01) between pre- and post-chemotherapy samples and among the regulated functions were the JNK cascade and cell death. Unsupervised hierarchical clustering identified one branch comprising exclusively, eight pre-chemotherapy samples and another branch, including the former correspondent eight post-chemotherapy samples and other 16 paired pre/post-chemotherapy samples. No differences in clinical and tumor parameters could explain this clustering. Another group of 11 patients with paired samples had expression of selected genes determined by real-time RT-PCR and CTGF and DUSP1 were confirmed more expressed in post- as compared to pre-chemotherapy samples. After neoadjuvant chemotherapy some residual samples may retain their molecular signature while others present significant changes in their gene expression, probably induced by the treatment. CTGF and DUSP1 overexpression in residual samples may be a reflection of resistance to further administration of AC regimen.
Koike Folgueira
Maria Aparecida Azevedo
MA
Faculdade de Medicina da Universidade de São Paulo, Departamento de Radiologia, Disciplina de Oncologia, São Paulo, SP, Brasil. makoike@lim24.fm.usp.br
Brentani
Helena
H
Carraro
Dirce Maria
DM
De Camargo Barros Filho
Mateus
M
Hirata Katayama
Maria Lucia
ML
Santana de Abreu
Ana Paula
AP
Mantovani Barbosa
Edson
E
De Oliveira
Célia Tosello
CT
Patrão
Diogo F C
DF
Mota
Louise D
LD
Netto
Mario Mourão
MM
Caldeira
José Roberto Figaro
JR
Brentani
Maria Mitzi
MM
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D055513:Connective Tissue Growth Factor / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics; D003520:Cyclophosphamide / Q000008:administration & dosage; D004317:Doxorubicin / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D054638:Dual Specificity Phosphatase 1 / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics; D005260:Female; D015870:Gene Expression / Q000187:drug effects*; D020869:Gene Expression Profiling; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D018365:Neoplasm, Residual; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics
D014408:Biomarkers, Tumor; C526317:CCN2 protein, human; D055513:Connective Tissue Growth Factor; D004317:Doxorubicin; D003520:Cyclophosphamide; D048670:MAP Kinase Kinase 4; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1