Increased metastasis with loss of E2F2 in Myc-driven tumors.

Yuwanita, Inez; Barnes, Danielle; Monterey, Michael D; O'Reilly, Sandra; Andrechek, Eran R

Yuwanita, Inez; Barnes, Danielle; Monterey, Michael D; O'Reilly, Sandra; Andrechek, Eran R.

Afiliación

Yuwanita I; Department of Physiology, Michigan State University, East Lansing, MI48824, Michigan, USA.
Barnes D; Department of Physiology, Michigan State University, East Lansing, MI48824, Michigan, USA.
Monterey MD; Department of Physiology, Michigan State University, East Lansing, MI48824, Michigan, USA.
O'Reilly S; Department of Physiology, Michigan State University, East Lansing, MI48824, Michigan, USA.
Andrechek ER; Department of Physiology, Michigan State University, East Lansing, MI48824, Michigan, USA.

Oncotarget ; 6(35): 38210-24, 2015 Nov 10.

Article en En | MEDLINE | ID: mdl-26474282

RESUMEN

In human breast cancer, mortality is associated with metastasis to distant sites. Therefore, it is critical to elucidate the biological mechanisms that underlie tumor progression and metastasis. Using signaling pathway signatures we previously predicted a role for E2F transcription factors in Myc induced tumors. To test this role we interbred MMTV-Myc transgenic mice with E2F knockouts. Surprisingly, we observed that the loss of E2F2 sharply increased the percentage of lung metastasis in MMTV-Myc transgenic mice. Examining the gene expression profile from these tumors, we identified genetic components that were potentially involved in mediating metastasis. These genes were filtered to uncover the genes involved in metastasis that also impacted distant metastasis free survival in human breast cancer. In order to elucidate the mechanism by which E2F2 loss enhanced metastasis we generated knockdowns of E2F2 in MDA-MB-231 cells and observed increased migration in vitro and increased lung colonization in vivo. We then examined genes that were differentially regulated between tumors from MMTV-Myc, MMTV-Myc E2F2-/-, and lung metastases samples and identified PTPRD. To test the role of PTPRD in E2F2-mediated breast cancer metastasis, we generated a knockdown of PTPRD in MDA-MB-231 cells. We noted that decreased levels of PTPRD resulted in decreased migration in vitro and decreased lung colonization in vivo. Taken together, these data indicate that E2F2 loss results in increased metastasis in breast cancer, potentially functioning through a PTPRD dependent mechanism.

Asunto(s)

Neoplasias de la Mama/metabolismo; Neoplasias de la Mama/patología; Factor de Transcripción E2F2/deficiencia; Factor de Transcripción E2F2/metabolismo; Genes myc; Neoplasias Pulmonares/metabolismo; Neoplasias Pulmonares/secundario; Animales; Neoplasias de la Mama/genética; Movimiento Celular; Modelos Animales de Enfermedad; Factor de Transcripción E2F2/genética; Femenino; Perfilación de la Expresión Génica/métodos; Regulación Neoplásica de la Expresión Génica; Redes Reguladoras de Genes; Humanos; Neoplasias Pulmonares/genética; Células MCF-7; Ratones Noqueados; Ratones Desnudos; Ratones Transgénicos; Invasividad Neoplásica; Mapas de Interacción de Proteínas; Interferencia de ARN; Proteínas Tirosina Fosfatasas Clase 2 Similares a Receptores/genética; Proteínas Tirosina Fosfatasas Clase 2 Similares a Receptores/metabolismo; Transducción de Señal; Factores de Tiempo; Transfección

Palabras clave

E2F transcription factors; MMTV-Myc; PTPRD; gene expression; metastasis

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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias de la Mama / Genes myc / Factor de Transcripción E2F2 / Neoplasias Pulmonares Tipo de estudio: Prognostic_studies Límite: Animals / Female / Humans Idioma: En Revista: Oncotarget Año: 2015 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos

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