RESUMO
Previously, we showed the association of neoadjuvant chemotherapy (NAC) response with changing the expression vector (increase or decrease) of multidrug resistance genes (MDR) in breast tumors during chemotherapy. The aim of the present study was to evaluate the relation between changes in the expression vector of MDR genes and distant metastasis-free survival. Patients (n = 120) with breast cancer (T1-4N0-3M0) treated by 2-4 cycles of NAC (CAX, FAC, and taxane regimes) and 4 cycles of adjuvant chemotherapy (FAC) were included. TaqMan-based quantitative reverse transcriptase PCR (qRT-PCR) was used to estimate the expression of the following MDR genes: ABCB1, ABCC1, ABCC2, ABCC5, ABCG1, ABCG2, GSTP1, and MVP--in biopsies before NAC and in tumor samples after chemotherapy. Comparing the corresponding expression levels allowed us to identify the vector of expression change during NAC. The results showed that 5-year distant metastasis-free survival was 73-78% in patients with a decrease in ABCB1, ABCC2, and ABCG1 expression. The up-regulation of these genes during NAC was related to a significant decrease (up to 50-55%) in metastasis-free survival (Kaplan-Meier analysis: log-rank p value = 0.006-0.03). The association of changing the expression vector of MDR genes with metastasis-free survival did not depend on tumor size, lymph node involvement, histological form, receptor status, molecular subtype, and others clinicopathological parameters of breast cancer. The obtained data suggest that changing the expression vector of MDR genes in breast tumors during NAC may be used as a new potential prognostic marker of breast cancer. An increase in tumor expression of ABCB1, ABCC2, and ABCG1 during chemotherapy is a factor of poor prognosis, whereas down-regulation of these genes--a favorable prognostic marker.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Resistência a Múltiplos Medicamentos/genética , Resistencia a Medicamentos Antineoplásicos/genética , Terapia Neoadjuvante/métodos , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Biomarcadores Tumorais/análise , Neoplasias da Mama/química , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Quimioterapia Adjuvante , Ciclofosfamida/administração & dosagem , Intervalo Livre de Doença , Regulação para Baixo , Doxorrubicina/administração & dosagem , Feminino , Fluoruracila/administração & dosagem , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Proteína 2 Associada à Farmacorresistência Múltipla , Estadiamento de Neoplasias , Valor Preditivo dos Testes , Prognóstico , Regulação para CimaRESUMO
For the first time in a comparative perspective the epigenetic status of the benign proliferative processes, breast cancer, and metastases to regional lymph nodes was studied using DNA methylation microarray "GoldenGate Cancer Panel I" ("Illumina", USA). The functional groups of differentially methylated genes were identified in each set of samples. The genes that regulate cell proliferation and mobility were methylated in samples with benign proliferative processes. An aberrant methylation of the genes responsible for cell differentiation and proliferation, as well as protein phosphorylation and cell mobility was observed in the samples with malignant phenotype. Differential methylation of the genes that regulate cell adhesion, the formation of anatomical structures, angiogenesis, immune response, signal transduction, and protein phosphorylation was found in the samples with metastases to regional lymph nodes in comparison with the morphologically unaltered breast epithelium. The tissues from the benign proliferative processes and metastases to regional lymph nodes were generally characterized by a relatively lower level of epigenetic variability in comparison with the tissues of the primary tumor.
Assuntos
Neoplasias da Mama/patologia , Transformação Celular Neoplásica/genética , Metilação de DNA/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Adesão Celular/genética , Proliferação de Células , Epigênese Genética/genética , Feminino , Humanos , Metástase Neoplásica , Estadiamento de Neoplasias , Neovascularização Patológica/genética , Análise de Sequência com Séries de Oligonucleotídeos , Fosforilação/genéticaRESUMO
This study involved 525 breast cancer (BC) patients of T2-4N0-2M0 stages at the age of 35 years and older. Significant differences in clinical and pathological characteristics between premenopausal and postmenopausal BC patients were found. Mostly marked differences were shown for positive lymph node correlation with distant metastasis, multicentric growth and local recurrence depending on menopause status. The prevalence of various morphological structures in primary tumors was appeared to be associated with different forms of tumor progression in pre- and postmenopausal women. We have studied polymorphisms in 15 genes involved in major cancer related pathways (apoptosis, interleukins, folate metabolism enzymes genes). We found that variant genotypes of MTHFR and DHFR genes were associated with an increased BC risk among premenopausal women while polymorphism in IL-18, p53 genes were associated with BC among postmenopausal women. These results demonstrate novel biological information, which points the different mechanisms contributed to breast cancer progression in premenopausal and postmenopausal women.
