RESUMEN

Understanding what drives breast tumor progression is of utmost importance for blocking tumor metastasis; we have identified that semaphorin 7a is a potent driver of ductal carcinoma in situ (DCIS) progression. Semaphorin 7a is a glycophosphatidylinositol membrane-anchored protein that promotes attachment and spreading in multiple cell types. Here, we show that increased expression of SEMA7A occurs in a large percentage of breast cancers and is associated with decreased overall and distant metastasis-free survival. In both in vitro and in vivo models, short hairpin-mediated silencing of SEMA7A reveals roles for semaphorin 7a in the promotion of DCIS growth, motility and invasion as well as lymphangiogenesis in the tumor microenvironment. Our studies also uncover a relationship between COX-2 and semaphorin 7a expression and suggest that semaphorin 7a promotes tumor cell invasion on collagen and lymphangiogenesis via activation of ß1-integrin receptor. Our results suggest that semaphorin 7a may be novel target for blocking breast tumor progression.

Asunto(s)

Antígenos CD/genética , Neoplasias de la Mama/genética , Carcinoma Intraductal no Infiltrante/genética , Ciclooxigenasa 2/genética , Neoplasias Mamarias Animales/genética , Semaforinas/genética , Animales , Antígenos CD/administración & dosificación , Neoplasias de la Mama/patología , Carcinoma Intraductal no Infiltrante/patología , Movimiento Celular/genética , Ciclooxigenasa 2/biosíntesis , Progresión de la Enfermedad , Femenino , Proteínas Ligadas a GPI/administración & dosificación , Proteínas Ligadas a GPI/genética , Regulación Neoplásica de la Expresión Génica , Pleiotropía Genética , Humanos , Linfangiogénesis/genética , Neoplasias Mamarias Animales/patología , Ratones , Semaforinas/administración & dosificación , Transducción de Señal