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Breast Cancer Res Treat ; 132(2): 487-98, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21647677

RESUMO

Normal mammary gland homeostasis requires the coordinated regulation of protein signaling networks. However, we have little prospective information on whether activation of protein signaling occurs in premalignant mammary epithelial cells, as represented by cells with cytological atypia from women who are at high risk for breast cancer. This information is critical for understanding the role of deregulated signaling pathways in the initiation of breast cancer and for developing targeted prevention and/or treatment strategies for breast cancer in the future. In this pilot and feasibility study, we examined the expression of 52 phosphorylated, total, and cleaved proteins in 31 microdissected Random Periareolar Fine Needle Aspiration (RPFNA) samples by high-throughput Reverse Phase Protein Microarray. Unsupervised hierarchical clustering analysis indicated the presence of four clusters of proteins that represent the following signaling pathways: (1) receptor tyrosine kinase/Akt/mammalian target of rapamycin (RTK/Akt/mTOR), (2) RTK/Akt/extracellular signal-regulated kinase (RTK/Akt/ERK), (3) mitochondrial apoptosis, and (4) indeterminate. Clusters 1 through 3 comprised moderately to highly expressed proteins, while Cluster 4 comprised proteins that are lowly expressed in a majority of RPFNA samples. Our exploratory study showed that the interlinked components of mitochondrial apoptosis pathway are highly expressed in all mammary epithelial cells obtained from high-risk women. In particular, the expression levels of anti-apoptotic Bcl-xL and pro-apoptotic Bad are positively correlated in both non-atypical and atypical samples (unadjusted P < 0.0001), suggesting a delicate balance between the pro-apoptotic and anti-apoptotic regulation of cell proliferation during the early steps of mammary carcinogenesis. Our feasibility study suggests that the activation of key proteins along the RTK/Akt pathway may tip this balance to cell survival. Taken together, our results demonstrate the feasibility of mapping proteomic signaling networks in limited RPFNA samples obtained from high-risk women and the promise of developing rational drug targets or preventative strategies for breast cancer in future proteomic studies with a larger cohort of high-risk women.


Assuntos
Proteínas Reguladoras de Apoptose/análise , Neoplasias da Mama/química , Proteínas de Ciclo Celular/análise , Glândulas Mamárias Humanas/química , Proteômica , Transdução de Sinais , Adulto , Idoso , Apoptose , Biópsia por Agulha Fina , Neoplasias da Mama/patologia , Sobrevivência Celular , Análise por Conglomerados , Estudos de Viabilidade , Feminino , Ensaios de Triagem em Larga Escala , Humanos , Modelos Logísticos , Glândulas Mamárias Humanas/patologia , Microdissecção , Pessoa de Meia-Idade , North Carolina , Projetos Piloto , Estudos Prospectivos , Análise Serial de Proteínas , Proteômica/métodos , Medição de Risco , Fatores de Risco
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