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.

microRNA-143/145 loss induces Ras signaling to promote aggressive Pten-deficient basal-like breast cancer

“…This is in stark contrast to multiple other mammary tumor models in which TICs were readily identified by our group and others (13,29,30,(60)(61)(62). One possible explanation is that AME tumor cells are dependent on estrogen signaling, thus unable to survive and proliferate in recipient mice without exogenous β-estradiol.…”

“…To identify TICs, mammary tumors were dissociated into single cells using collagenase digestion, lineage depleted, sorted on the basis of specific cell surface markers, serially diluted, mixed with matrigel, and transplanted into mammary glands of young, immunocompromised mice. Using these conditions, we previously identified TICs in mouse models of her2/neu, wnt1, mammary-specific rb loss, p53 loss, and pten/p53 double mutants (13,29,30 Table 2). …”

Intersection of retinoblastoma tumor suppressor function, stem cells, metabolism, and inflammation

“…Conversely, enhanced mitochondrial activity also increases ROS production associated with elevated oxygen consumption. The RB–E2F complex is known to directly suppress the expression of oxidative metabolism‐related enzymes and mitochondrial protein translation genes . Disruption of this complex therefore seems to provoke oxidative metabolism, such as the tricarboxylic acid cycle and FAO.…”

The Antibiotic Drug Tigecycline: A Focus on its Promising Anticancer Properties

“…As the mitochondrial energy metabolism provides distinct pro-survival benefits to diffuse large B-cell lymphomas (DLBCLs), pharmacological perturbation of the mitochondrial translation pathway with TIG is proved to be selectively toxic to DLBCL cell lines (Norberg et al, 2016). In addition, another group has identified that TIG could serve as a potential new therapeutic drug for treatment of retinoblastoma (RB1) -deficient breast cancer (Jones et al, 2016). Therefore, an important consideration in anti-cancer fields will be addressing mitochondrial signaling modulation with chemical compounds.…”