RESUMEN
Chemotherapeutic response is critical for the successful treatment and good prognosis in cancer patients. In this study, we analysed the gene expression profiles of preoperative samples from oestrogen receptor (ER)-negative breast cancer patients with different responses to taxane-anthracycline-based (TA-based) chemotherapy, and identified a group of genes that was predictive. Pregnancy specific beta-1-glycoprotein 1 (PSG1) played a central role within signalling pathways of these genes. Inhibiting PSG1 can effectively reduce chemoresistance via a transforming growth factor-ß (TGF-ß)-related pathway in ER-negative breast cancer cells. Drug screening then identified dicumarol (DCM) to target the PSG1 and inhibit chemoresistance to TA-based chemotherapy in vitro, in vivo, and in clinical samples. Taken together, this study highlights PSG1 as an important mediator of chemoresistance, whose effect could be diminished by DCM.
Asunto(s)
Anticoagulantes/uso terapéutico , Neoplasias de la Mama/genética , Dicumarol/uso terapéutico , Glicoproteínas beta 1 Específicas del Embarazo/antagonistas & inhibidores , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Hidrocarburos Aromáticos con Puentes/uso terapéutico , Línea Celular Tumoral , Resistencia a Antineoplásicos , Femenino , Humanos , Glicoproteínas beta 1 Específicas del Embarazo/genética , Glicoproteínas beta 1 Específicas del Embarazo/metabolismo , Taxoides/uso terapéutico , Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
Intrauterine administration of 100 arbitrary units (AU) of purified monospecific rabbit anti murine pregnancy specific beta 1-glycoprotein antibodies resulted in the loss of the fetuses in pregnant mice (14 out of 14). By contrast, a similar treatment with 100 AU of rabbit anti murine pregnancy-associated alpha 2-glycoprotein had an effect similar to saline on the outcome of pregnancy. Intravenous administration of 1000 AU of rabbit anti murine pregnancy specific beta 1-glycoprotein during pregnancy in mice had no effect on the outcome of pregnancy.