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Background <p>Recent research from our group has shown that the overexpression of the wild-type RAS-family GTPase <i>RRAS2</i> drives the onset of triple-negative breast cancer (TNBC) in mice following one or more pregnancies. This phenomenon mirrors human TNBC, where <i>RRAS2</i> is overexpressed in approximately 75% of cases, particularly in tumors associated with the postpartum period. These findings underscore the relevance of R-RAS2 in TNBC development and progression.</p> Methods <p>We conducted RNA sequencing on tumors derived from conditional knock-in mice overexpressing human wild-type <i>RRAS2</i> to identify the somatic mutation landscape associated with TNBC development in these mice. Additionally, we developed a TNBC cell line from <i>RRAS2</i>-overexpressing mice, enabling loss-of-function studies to investigate the role of R-RAS2 in various pathobiological parameters of TNBC cells, including cell migration, invasiveness, metabolic activity, and metastatic spread. Furthermore, proteomic analysis of a freshly isolated tumor identified plasma membrane receptors interacting with R-RAS2.</p> Results <p>Our findings demonstrate that TNBC driven by <i>RRAS2</i> overexpression exhibits a pattern of somatic mutations similar to those observed in human breast cancer, particularly in genes involved in stemness, extracellular matrix interactions, and actin cytoskeleton regulation. Proteomic analysis revealed that wild-type R-RAS2 interacts with 245 membrane-associated proteins, including key solute carriers involved in cell metabolism (CD98/LAT1, GLUT1, and basigin), adhesion and matrix interaction proteins (CD44, EpCAM, MCAM, ICAM1, integrin-α6, and integrin-β1), and stem cell markers (β1-catenin, α1-catenin, PTK7, and CD44). We show that R-RAS2 regulates CD98/LAT1 transporter-mediated mTOR pathway activation and mediates CD44-dependent cancer cell migration and invasion, thus providing a mechanism by which R-RAS2 promotes breast cancer cell metastasis.</p> Conclusions <p>R-RAS2 associates with CD44, CD98/LAT1, and other plasma membrane receptors to regulate metabolic activity, actin cytoskeleton reorganization, cell migration, invasion, and distant metastasis formation in TNBC. These findings establish R-RAS2 as a central driver of TNBC malignancy and highlight its potential as a promising therapeutic target, particularly in aggressive, postpartum-associated breast cancers.</p>

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The R-RAS2 GTPase is a signaling hub in triple-negative breast cancer cell metabolism and metastatic behavior

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月12日

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  • Claudia Cifuentes,
  • Lydia Horndler,
  • Pilar Grosso,
  • Clara L Oeste,
  • Alejandro M. Hortal,
  • Jennifer Castillo,
  • Isabel Fernández-Pisonero,
  • Alberto Paradela,
  • Xosé Bustelo,
  • Balbino Alarcón

摘要

Background

Recent research from our group has shown that the overexpression of the wild-type RAS-family GTPase RRAS2 drives the onset of triple-negative breast cancer (TNBC) in mice following one or more pregnancies. This phenomenon mirrors human TNBC, where RRAS2 is overexpressed in approximately 75% of cases, particularly in tumors associated with the postpartum period. These findings underscore the relevance of R-RAS2 in TNBC development and progression.

Methods

We conducted RNA sequencing on tumors derived from conditional knock-in mice overexpressing human wild-type RRAS2 to identify the somatic mutation landscape associated with TNBC development in these mice. Additionally, we developed a TNBC cell line from RRAS2-overexpressing mice, enabling loss-of-function studies to investigate the role of R-RAS2 in various pathobiological parameters of TNBC cells, including cell migration, invasiveness, metabolic activity, and metastatic spread. Furthermore, proteomic analysis of a freshly isolated tumor identified plasma membrane receptors interacting with R-RAS2.

Results

Our findings demonstrate that TNBC driven by RRAS2 overexpression exhibits a pattern of somatic mutations similar to those observed in human breast cancer, particularly in genes involved in stemness, extracellular matrix interactions, and actin cytoskeleton regulation. Proteomic analysis revealed that wild-type R-RAS2 interacts with 245 membrane-associated proteins, including key solute carriers involved in cell metabolism (CD98/LAT1, GLUT1, and basigin), adhesion and matrix interaction proteins (CD44, EpCAM, MCAM, ICAM1, integrin-α6, and integrin-β1), and stem cell markers (β1-catenin, α1-catenin, PTK7, and CD44). We show that R-RAS2 regulates CD98/LAT1 transporter-mediated mTOR pathway activation and mediates CD44-dependent cancer cell migration and invasion, thus providing a mechanism by which R-RAS2 promotes breast cancer cell metastasis.

Conclusions

R-RAS2 associates with CD44, CD98/LAT1, and other plasma membrane receptors to regulate metabolic activity, actin cytoskeleton reorganization, cell migration, invasion, and distant metastasis formation in TNBC. These findings establish R-RAS2 as a central driver of TNBC malignancy and highlight its potential as a promising therapeutic target, particularly in aggressive, postpartum-associated breast cancers.