RESUMO
High-grade serous ovarian carcinoma (HGSOC) and basal-like breast cancer (BLBC) share many features including TP53 mutations, genomic instability and poor prognosis. We recently reported that Elafin is overexpressed by HGSOC and is associated with poor overall survival. Here, we confirm that Elafin overexpression is associated with shorter survival in 1000 HGSOC patients. Elafin confers a proliferative advantage to tumor cells through the activation of the MAP kinase pathway. This mitogenic effect can be neutralized by RNA interference, specific antibodies and a MEK inhibitor. Elafin expression in patient-derived samples was also associated with chemoresistance and strongly correlates with bcl-xL expression. We extended these findings into the examination of 1100 primary breast tumors and six breast cancer cell lines. We observed that Elafin is overexpressed and secreted specifically by BLBC tumors and cell lines, leading to a similar mitogenic effect through activation of the MAP kinase pathway. Here too, Elafin overexpression is associated with poor overall survival, suggesting that it may serve as a biomarker and therapeutic target in this setting.
Assuntos
Neoplasias da Mama/genética , Cistadenocarcinoma Seroso/genética , Elafina/genética , Neoplasias Ovarianas/genética , Western Blotting , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células , Cistadenocarcinoma Seroso/metabolismo , Cistadenocarcinoma Seroso/patologia , Elafina/metabolismo , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Sistema de Sinalização das MAP Quinases/genética , Células MCF-7 , Avaliação de Resultados em Cuidados de Saúde/estatística & dados numéricos , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Prognóstico , Modelos de Riscos Proporcionais , Proteômica , Interferência de RNA , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteína bcl-X/genética , Proteína bcl-X/metabolismoRESUMO
Posttranslational modification of peptide antigens has been shown to alter the ability of T cells to recognize major histocompatibility complex (MHC) class I-restricted peptides. However, the existence and origin of naturally processed phosphorylated peptides presented by MHC class I molecules have not been explored. By using mass spectrometry, significant numbers of naturally processed phosphorylated peptides were detected in association with several human MHC class I molecules. In addition, CD8(+) T cells could be generated that specifically recognized a phosphorylated epitope. Thus, phosphorylated peptides are part of the repertoire of antigens available for recognition by T cells in vivo.
Assuntos
Apresentação de Antígeno , Antígenos de Histocompatibilidade Classe I/imunologia , Fosfopeptídeos/imunologia , Fosfopeptídeos/metabolismo , Alelos , Sequência de Aminoácidos , Animais , Antígenos/química , Antígenos/imunologia , Antígenos/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Linhagem Celular , Citocinas/metabolismo , Epitopos de Linfócito T/química , Epitopos de Linfócito T/imunologia , Epitopos de Linfócito T/metabolismo , Antígenos HLA/imunologia , Humanos , Interferon gama/biossíntese , Espectrometria de Massas , Camundongos , Camundongos Endogâmicos C57BL , Fosfopeptídeos/químicaRESUMO
Superantigens (SAgs) activate TH cells and induce their differentiation into cytokine-producing effector cells. Supranormal cytokine production is characteristic of SAg-induced polyclonal TH activation. Study of this interaction has focused upon TH cell function to the relative exclusion of other lymphocyte populations. SAgs also impact cells dependent upon TH cells for their differentiation and disrupt the normal homeostasis of the immune system. In this report, several changes in lymphocyte biology that result from SAg activation of TH cells are described. SCID mice, reconstituted with the SAg-expressing cells of DBA/2J mice, were employed as secondary recipients of SAg-reactive TH cells. Significant increases in serum IgM and IgG2a production were noted after the transfer of SAg-reactive It cells. Both B and CD8 T lymphocyte numbers increased with those of CD8 T cells surpassing levels found in normal mice. These results illustrate the ability of the TH-SAg interaction to disrupt B and CD8+ T lymphocyte homeostasis.
