TBC1 domain-containing proteins are frequently involved in triple-negative breast cancers in connection with the induction of a glycolytic phenotype

Sep 21, 2026

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Metabolic plasticity underpins cancer aggressiveness, making metabolic rewiring an attractive therapeutic direction. Because cellular metabolism is coordinated through membrane trafficking, researchers examined TBC1 domain-containing proteins (TBC1Ds) and their roles beyond canonical RAB-GAP regulation. They found that multiple TBC1D genes are upregulated in triple-negative breast cancer and correlate with prognosis, linking prognostic TBC1Ds to elevated glycolytic metabolism. Functional studies showed causal control of a glycolytic phenotype, including a TBC1D7 effect independent of TSC1/TSC2-mTORC1 signaling, supporting biomarker-based therapy stratification.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages14

Reading Time35 min

AccessFree to download

Introduction

Metabolic plasticity and the Warburg effect

Breast cancer subtypes and TNBC prognosis

Metabolic heterogeneity within TNBC

Study rationale and protein functions

TBC1Ds and RAB-GAP regulation

Mutations in catalytic residues and altered function

Results summary

Higher TBC1D expression and prognosis in TNBC

Correlation with glycolytic metabolism

Causal role of top TBC1D hits

TBC1D7 mechanism independent of mTORC1

Implications for therapy decision-making

[www.nature.com/cddis](www.nature.com/cddis) ARTICLE OPEN TBC1 domain-containing proteins are frequently involved in triple-negative breast cancers in connection with the induction of a glycolytic phenotype Mariadomenica Lupi 1,2,8, Daniele Avanzato 1,6,8, Stefano Confalonieri3,8, Flavia Martino 1,2, Rosa Pennisi 1,2, Emanuela Pupo 2, Valentina Audrito 4, Stefano Freddi 3,5, Giovanni Bertalot 3,7, Francesca Montani 3, Bronislava Matoskova3, Sara Sigismund 3,5, Pier Paolo Di Fiore 3,5,9 ✉ and Letizia Lanzetti 1,2,9 ✉ © The Author(s) 2024 | | Metabolic plasticity is a hallmark of cancer, and metabolic alterations represent a promising therapeutic target. Since cellular metabolism is controlled by membrane trafﬁc at multiple levels, we investigated the involvement of TBC1 domain-containing proteins (TBC1Ds) in the regulation of cancer metabolism. These proteins are characterized by the presence of a RAB-GAP domain, the TBC1 domain, and typically function as attenuators of RABs, the master switches of membrane trafﬁc. However, a number of TBC1Ds harbor mutations in their catalytic residues, predicting biological functions different from direct regulation of RAB activities. Herein, we report that several genes encoding for TBC1Ds are expressed at higher levels in triple-negative breast cancers (TNBC) vs. other subtypes of breast cancers (BC), and predict prognosis. Orthogonal transcriptomics/metabolomics analysis revealed that the expression of prognostic TBC1Ds correlates with elevated glycolytic metabolism in BC cell lines. In-depth investigations of the three top hits from the previous analyses (TBC1D31, TBC1D22B and TBC1D7) revealed that their elevated expression is causal in determining a glycolytic phenotype in TNBC cell lines. We further showed that the impact of TBC1D7 on glycolytic metabolism of BC cells is independent of its known participation in the TSC1/TSC2 complex and consequent downregulation of mTORC1 activity. Since TBC1D7 behaves as an independent prognostic biomarker in TNBC, it could be used to distinguish good prognosis patients who could be spared aggressive therapy from those with a poor prognosis who might beneﬁt from anti-glycolytic targeted therapies. Together, our results highlight how TBC1Ds connect disease aggressiveness with metabolic alterations in TNBC. Given the high level of heterogeneity among this BC subtype, TBC1Ds could represent important tools in predicting prognosis and | | | --- | --- | --- | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | guiding therapy decision-making. | | | | | | | | | | | | Cell Death and Disease (2024)15:647; [https://doi.org/10.1038/s41419-024-07037-2](https://doi.org/10.1038/s41419-024-07037-2) | | | | | | INTRODUCTION Cancers meet their high metabolic demands, both anabolic and catabolic, through a variety of adaptations, globally deﬁned as“metabolic plasticity” [1] . The best characterized metabolic alteration in cancer is the elevation of aerobic glycolysis, the socalled Warburg effect, a process whereby pyruvate is reduced to lactate even in the presence of oxygen [2] . The Warburg effect is proposed to confer growing advantages to cancer cells mostly by increasing the production of anabolic intermediates, through heightened glycolytic ﬂux [3, 4] . Breast cancer (BC) is the most frequently diagnosed neoplasia worldwide, accounting for ~12% of all cancer diagnoses and ~7% of cancer-related deaths [5] . It is a phenotypically and molecularly heterogenous disease, which can be categorized into molecular subtypes based on the expression of the estrogen and progesterone receptors (ER and PGR, respectively), and the ampliﬁcation of the HER2 oncogene (HUGO: ERBB2) . Luminal BCs are ER+/HER2-; HER2+ BCs display ampliﬁcation of HER2, regardless of the ER/PGR status; triple-negative BCs (TNBCs) are negative for the expre

FAQs

What question does the study address about TBC1 domain-containing proteins?

The study investigates how TBC1 domain-containing proteins contribute to cancer metabolism and whether they are involved in shaping metabolic phenotypes in triple-negative breast cancer.

How are TBC1D genes related to triple-negative breast cancer prognosis?

Several genes encoding TBC1Ds show higher expression in triple-negative breast cancers than in other breast cancer subtypes, and their expression levels correlate with patient prognosis.

What is the key finding linking TBC1Ds to glycolysis in TNBC?

Orthogonal transcriptomics/metabolomics analyses indicate that prognostic TBC1Ds align with elevated glycolytic metabolism, and follow-up experiments demonstrate that top TBC1D genes causally drive a glycolytic phenotype in TNBC cell lines.

Sep 21, 2026

Upload by Levi