Basal-A Triple-Negative Breast Cancer Cells Selectively Rely on RNA Splicing for Survival.

Autor:	Chan S; Division of Computational Biomedicine, Department of Surgery, Boston University School of Medicine, Boston, Massachusetts.; Division of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts., Sridhar P; Division of Computational Biomedicine, Department of Surgery, Boston University School of Medicine, Boston, Massachusetts.; Division of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts., Kirchner R; Bioinformatics Core, Harvard T.H. Chan School of Public Health, Boston, Massachusetts., Lock YJ; Division of Computational Biomedicine, Department of Surgery, Boston University School of Medicine, Boston, Massachusetts.; Division of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts., Herbert Z; Molecular Biology Core Facilities, Dana-Farber Cancer Institute, Boston, Massachusetts., Buonamici S; H3 Biomedicine Inc., Cambridge, Massachusetts., Smith P; H3 Biomedicine Inc., Cambridge, Massachusetts., Lieberman J; Program in Cellular and Molecular Medicine, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts. fabio.petrocca@gmail.com judy.lieberman@childrens.harvard.edu., Petrocca F; Division of Computational Biomedicine, Department of Surgery, Boston University School of Medicine, Boston, Massachusetts. fabio.petrocca@gmail.com judy.lieberman@childrens.harvard.edu.; Division of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts.
Jazyk:	angličtina
Zdroj:	Molecular cancer therapeutics [Mol Cancer Ther] 2017 Dec; Vol. 16 (12), pp. 2849-2861. Date of Electronic Publication: 2017 Sep 06.
DOI:	10.1158/1535-7163.MCT-17-0461
Abstrakt:	Prognosis of triple-negative breast cancer (TNBC) remains poor. To identify shared and selective vulnerabilities of basal-like TNBC, the most common TNBC subtype, a directed siRNA lethality screen was performed in 7 human breast cancer cell lines, focusing on 154 previously identified dependency genes of 1 TNBC line. Thirty common dependency genes were identified, including multiple proteasome and RNA splicing genes, especially those associated with the U4/U6.U5 tri-snRNP complex (e.g., PRPF8, PRPF38A ). PRPF8 or PRPF38A knockdown or the splicing modulator E7107 led to widespread intronic retention and altered splicing of transcripts involved in multiple basal-like TNBC dependencies, including protein homeostasis, mitosis, and apoptosis. E7107 treatment suppressed the growth of basal-A TNBC cell line and patient-derived basal-like TNBC xenografts at a well-tolerated dose. The antitumor response was enhanced by adding the proteasome inhibitor bortezomib. Thus, inhibiting both splicing and the proteasome might be an effective approach for treating basal-like TNBC. Mol Cancer Ther; 16(12); 2849-61. ©2017 AACR . (©2017 American Association for Cancer Research.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu