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Author Spotlight: Advancing Techniques and Discoveries in Protein Synthesis and Assembly Through Innovative Mitochondrial Research
Published on: June 7, 2024
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.
Insights
Retinoblastoma gene (RB1) loss in triple-negative breast cancer (TNBC) enhances mitochondrial function. The FDA-approved drug tigecycline effectively inhibits RB1-deficient TNBC cell growth and xenograft progression.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Triple-negative breast cancer (TNBC) lacks targeted therapies.
- Retinoblastoma tumor suppressor gene (RB1) loss is common in TNBC but not directly targetable.
- Identifying RB1 downstream vulnerabilities is crucial for therapeutic strategies.
Purpose of the Study:
- To investigate the functional consequences of RB1 loss in TNBC.
- To identify therapeutic vulnerabilities and drugs targeting RB1-deficient TNBC.
- To explore the role of mitochondrial protein translation (MPT) in RB1-deficient TNBC.
Main Methods:
- Murine models of combined Rb and p53 inactivation in mammary epithelial cells.
- Gene set enrichment analysis to identify upregulated pathways.
- Bioinformatic, functional, and biochemical assays to study RB1-E2F complex activity.
- Drug screening of FDA-approved compounds.
- In vitro and in vivo assays using TNBC cell lines and xenografts.
Main Results:
- Combined Rb/p53 deficiency induced claudin-low-like TNBC with specific gene amplifications.
- Rb/p53-deficient tumors exhibited elevated mitochondrial protein translation (MPT) pathway gene expression.
- RB1-E2F complexes directly regulate MPT gene transcription.
- Tigecycline (TIG), an MPT antagonist, potently inhibited Rb/p53-deficient TNBC cell proliferation.
- TIG demonstrated efficacy against both bulk and cancer stem cells, reducing xenograft growth.
- TIG showed synergistic effects with sulfasalazine.
Conclusions:
- RB1 deficiency promotes TNBC proliferation via enhanced mitochondrial function.
- Tigecycline is a promising, clinically approved therapeutic agent for RB1-deficient TNBC.
- Combined inhibition of MPT and cystine antiporter may offer a novel therapeutic approach for TNBC.
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