RB1 deficiency in triple-negative breast cancer induces mitochondrial protein translation
Robert A. Jones, … , Aaron Schimmer, Eldad Zacksenhaus
Robert A. Jones, … , Aaron Schimmer, Eldad Zacksenhaus
Published August 29, 2016
Citation Information: J Clin Invest. 2016;126(10):3739-3757. https://doi.org/10.1172/JCI81568.
View: Text | PDF
Research Article Oncology

RB1 deficiency in triple-negative breast cancer induces mitochondrial protein translation

Abstract

Triple-negative breast cancer (TNBC) includes basal-like and claudin-low subtypes for which no specific treatment is currently available. Although the retinoblastoma tumor-suppressor gene (RB1) is frequently lost together with TP53 in TNBC, it is not directly targetable. There is thus great interest in identifying vulnerabilities downstream of RB1 that can be therapeutically exploited. Here, we determined that combined inactivation of murine Rb and p53 in diverse mammary epithelial cells induced claudin-low–like TNBC with Met, Birc2/3-Mmp13-Yap1, and Pvt1-Myc amplifications. Gene set enrichment analysis revealed that Rb/p53-deficient tumors showed elevated expression of the mitochondrial protein translation (MPT) gene pathway relative to tumors harboring p53 deletion alone. Accordingly, bioinformatic, functional, and biochemical analyses showed that RB1-E2F complexes bind to MPT gene promoters to regulate transcription and control MPT. Additionally, a screen of US Food and Drug Administration–approved (FDA-approved) drugs identified the MPT antagonist tigecycline (TIG) as a potent inhibitor of Rb/p53-deficient tumor cell proliferation. TIG preferentially suppressed RB1-deficient TNBC cell proliferation, targeted both the bulk and cancer stem cell fraction, and strongly attenuated xenograft growth. It also cooperated with sulfasalazine, an FDA-approved inhibitor of cystine xCT antiporter, in culture and xenograft assays. Our results suggest that RB1 deficiency promotes cancer cell proliferation in part by enhancing mitochondrial function and identify TIG as a clinically approved drug for RB1-deficient TNBC.

Authors

Robert A. Jones, Tyler J. Robinson, Jeff C. Liu, Mariusz Shrestha, Veronique Voisin, YoungJun Ju, Philip E.D. Chung, Giovanna Pellecchia, Victoria L. Fell, SooIn Bae, Lakshmi Muthuswamy, Alessandro Datti, Sean E. Egan, Zhe Jiang, Gustavo Leone, Gary D. Bader, Aaron Schimmer, Eldad Zacksenhaus

×

Figure 3

Rb/p53-deficient mammary tumors show a high frequency of CD49f+CD24– TICs and genomic amplifications involving Met, Birc2/3-Mmp13-Yap1, and Pvt1-Myc.

Options: View larger image (or click on image) Download as PowerPoint
Rb/p53-deficient mammary tumors show a high frequency of CD49f+CD24– TIC...
(A) Flow cytometric profiles of normal mammary gland and p53Δ and RbΔp53Δ claudin-low mammary tumors with CD49f and CD24 cell-surface markers. (B) Gates used to isolate tumor cell populations (1°). FACS profiles of secondary tumors obtained from CD49floCD24lo (P1), CD49fhiCD24lo (P2), and CD49fhiCD24hi (P3) populations (2°). See Table 1 for TIC frequency. (C) Probe level images of copy number data showing high-level amplifications on chromosomes (Chrom) 6qA2, 9qA1, and 15qD1. (D) Integration of CNAs with gene expression identified genes regulated at the genomic and transcriptional levels, including Met, Pvt1, and Mmp13 amplification as well as Fhit deletion on chromosome 14qA1. Green (low); red (high). CN, copy number; mam, mammary; PE, phycoerythrin.