RESUMO
Progesterone receptor (PR) could activate transcriptional process involved in normal mammary gland proliferation and breast cancer development. Moreover, PR expression is an important marker of luminal breast cancer, which is associated with good prognosis and indicates better responding to endocrine therapies. The regulation of PR expression was studied mainly on its post-translational levels. In this study, we found PR was positively regulated by RNA-binding region-containing protein 1 (RNPC1), a RNA-binding protein, in PR positive breast cancer. Overexpression of RNPC1 increased, whereas knockdown of RNPC1 decreased, the level of PR protein and transcripts. Additionally, we demonstrated that RNPC1 could bind to PR mRNA via AU-rich elements (AREs) within PR 3'-untranslated region (3'-UTR) and then enhance PR mRNA stability. Moreover, we proved that progesterone-dependent PR functions which could induce breast cancer proliferation were enhanced by RNPC1, both in vitro and in vivo. Conclusively, we revealed a novel mechanism by which PR could be regulated by RNPC1 via stabilizing its mRNA.
Assuntos
Neoplasias da Mama/metabolismo , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/metabolismo , Receptores de Progesterona/metabolismo , Regiões 3' não Traduzidas/genética , Elementos Ricos em Adenilato e Uridilato/genética , Animais , Western Blotting , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Células MCF-7 , Camundongos Endogâmicos NOD , Camundongos SCID , Microscopia de Fluorescência , Progesterona/farmacologia , Progestinas/farmacologia , Ligação Proteica , Interferência de RNA , Estabilidade de RNA/genética , RNA Mensageiro/genética , Proteínas de Ligação a RNA/genética , Receptores de Progesterona/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Ensaios Antitumorais Modelo de Xenoenxerto/métodosRESUMO
Estrogen receptors (ERs), including ERα and ERß, mainly mediate the genotype effect of estrogen. ERα is highly expressed in most breast cancers. Endocrine therapy is the most effective and safety adjunctive therapy for ER positive breast cancers. RNPC1, an RNA binding protein (RBP), post-transcriptionally regulating gene expression, is emerging as a critical mechanism for gene regulation in mammalian cells. In this study, we revealed RNPC1's capability of regulating ERα expression. There was a significant correlation between RNPC1 and ERα expression in breast cancer tissues. Ectopic expression of RNPC1 could increase ERα transcript and expression in breast cancer cells, and vice versa. Consistent with this, RNPC1 was able to bind to ERα transcript to increase its stability. Furthermore, overexpression of ERα could decrease the level of RNPC1 transcript and protein. It suggested a novel mechanism by which ERα expression was regulated via stabilizing mRNA. A regulatory feedback loop between RNPC1 and ERα was proved. It indicated that RNPC1 played a crucial role in ERα regulation in ER-positive breast cancers via binding to ERα mRNA. These findings might provide new insights into breast cancer endocrine therapy and ERα research.
