RESUMEN
To elucidate the role of a type II transmembrane serine protease, ST14/Prss14, during breast cancer progression, we utilized publically accessible databases including TCGA, GEO, NCI-60, and CCLE. Survival of breast cancer patients with high ST14/Prss14 expression is significantly poor in estrogen receptor (ER) negative populations regardless of the ratios of ST14/Prss14 to its inhibitors, SPINT1 or SPINT2. In a clustering of 1085 selected EMT signature genes, ST14/Prss14 is located in the same cluster with CDH3, and closer to post-EMT markers, CDH2, VIM, and FN1 than to the pre-EMT marker, CDH1. Coexpression analyses of known ST14/Prss14 substrates and transcription factors revealed context dependent action. In cell lines, paradoxically, ST14/Prss14 expression is higher in the ER positive group and located closer to CDH1 in clustering. This apparent contradiction is not likely due to ST14/Prss14 expression in a cancer microenvironment, nor due to negative regulation by ER. Genes consistently coexpressed with ST14/Prss14 include transcription factors, ELF5, GRHL1, VGLL1, suggesting currently unknown mechanisms for regulation. Here, we report that ST14/Prss14 is an emerging therapeutic target for breast cancer where HER2 is not applicable. In addition we suggest that careful conclusions should be drawn not exclusively from the cell line studies for target development.
Asunto(s)
Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Receptores de Estrógenos/metabolismo , Serina Endopeptidasas/metabolismo , Biomarcadores de Tumor/genética , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/mortalidad , Línea Celular Tumoral , Proteínas de Unión al ADN/metabolismo , Transición Epitelial-Mesenquimal/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Glicoproteínas de Membrana/metabolismo , Persona de Mediana Edad , Pronóstico , Proteínas Inhibidoras de Proteinasas Secretoras/metabolismo , Proteínas Proto-Oncogénicas c-ets/metabolismo , Proteínas Represoras/metabolismo , Serina Endopeptidasas/genética , Factores de Transcripción/metabolismoRESUMEN
Epithin/PRSS14, a type II transmembrane serine protease, plays critical roles in cancer metastasis. Previously, we have reported that epithin/PRSS14 undergoes ectodomain shedding in response to phorbol myristate acetate (PMA) stimulation. In this study, we show that transforming growth factor-ß (TGF-ß) induces rapid epithin/PRSS14 shedding through receptor mediated pathway in 427.1.86 thymoma cells. Tumor necrosis factor-α converting enzyme (TACE) is responsible for this shedding. Amino acid sequence encompassing the putative shedding cleavage site of epithin/PRSS14 exhibit strong homology to the cleavage site of l-selectin, a known TACE substrate. TACE inhibitor, TAPI-0 and TACE siRNA greatly reduced TGF-ß-induced epithin/PRSS14 shedding. TGF-ß treatment induces translocation of intracellular pool of TACE to the membrane where epithin/PRSS14 resides. These findings suggest that TGF-ß induces epithin/PRSS14 shedding by mediating translocation of epithin/PRSS14 sheddase, TACE, to the membrane.