The mevalonate pathway contributes to breast primary tumorigenesis and lung metastasis
The mevalonate pathway plays an important role in breast cancer and other tumor types. However, many issues remain obscure as yet regarding its mechanism of regulation and action. In the present study, we report that the expression of mevalonate pathway enzymes is mediated by the RHO guanosine nucle...
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| Format: | Article |
| Language: | English |
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Wiley
2025-01-01
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| Series: | Molecular Oncology |
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| Online Access: | https://doi.org/10.1002/1878-0261.13716 |
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| author | Javier Conde Isabel Fernández‐Pisonero L. Francisco Lorenzo‐Martín Rocío García‐Gómez Berta Casar Piero Crespo Xosé R. Bustelo |
| author_facet | Javier Conde Isabel Fernández‐Pisonero L. Francisco Lorenzo‐Martín Rocío García‐Gómez Berta Casar Piero Crespo Xosé R. Bustelo |
| author_sort | Javier Conde |
| collection | DOAJ |
| description | The mevalonate pathway plays an important role in breast cancer and other tumor types. However, many issues remain obscure as yet regarding its mechanism of regulation and action. In the present study, we report that the expression of mevalonate pathway enzymes is mediated by the RHO guanosine nucleotide exchange factors VAV2 and VAV3 in a RAC1‐ and sterol regulatory element‐binding factor (SREBF)‐dependent manner in breast cancer cells. Furthermore, in vivo tumorigenesis experiments indicated that the two most upstream steps of this metabolic pathway [3‐hydroxy‐3‐methylglutaryl‐coenzyme A synthase 1 (HMGCS1) and 3‐hydroxy‐3‐methylglutaryl‐coenzyme A reductase (HMGCR)] are important for primary tumorigenesis, angiogenesis, and cell survival in breast cancer cells. HMGCR, but not HMGCS1, is also important for the extravasation and subsequent fitness of breast cancer cells in the lung parenchyma. Genome‐wide expression analyses revealed that HMGCR influences the expression of gene signatures linked to proliferation, metabolism, and immune responses. The HMGCR‐regulated gene signature predicts long‐term tumor recurrence but not metastasis in cohorts of nonsegregated and chemotherapy‐resistant breast cancer patients. These results reveal a hitherto unknown, VAV‐catalysis‐dependent mechanism involved in the regulation of the mevalonate pathway in breast cancer cells. They also identify specific mevalonate‐pathway‐dependent processes that contribute to the malignant features of breast cancer cells. |
| format | Article |
| id | doaj-art-2c7e929d5aea4d67b1d799eeae224d67 |
| institution | Kabale University |
| issn | 1574-7891 1878-0261 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Oncology |
| spelling | doaj-art-2c7e929d5aea4d67b1d799eeae224d672025-01-07T14:42:32ZengWileyMolecular Oncology1574-78911878-02612025-01-01191568010.1002/1878-0261.13716The mevalonate pathway contributes to breast primary tumorigenesis and lung metastasisJavier Conde0Isabel Fernández‐Pisonero1L. Francisco Lorenzo‐Martín2Rocío García‐Gómez3Berta Casar4Piero Crespo5Xosé R. Bustelo6Molecular Mechanisms of Cancer Program, Centro de Investigación del Cáncer Consejo Superior de Investigaciones Científicas (CSIC) and Universidad de Salamanca SpainMolecular Mechanisms of Cancer Program, Centro de Investigación del Cáncer Consejo Superior de Investigaciones Científicas (CSIC) and Universidad de Salamanca SpainMolecular Mechanisms of Cancer Program, Centro de Investigación del Cáncer Consejo Superior de Investigaciones Científicas (CSIC) and Universidad de Salamanca SpainCentro de Investigación Biomédica en Red de Cáncer (CIBERONC) Instituto de Salud Carlos III Madrid SpainCentro de Investigación Biomédica en Red de Cáncer (CIBERONC) Instituto de Salud Carlos III Madrid SpainCentro de Investigación Biomédica en Red de Cáncer (CIBERONC) Instituto de Salud Carlos III Madrid SpainMolecular Mechanisms of Cancer Program, Centro de Investigación del Cáncer Consejo Superior de Investigaciones Científicas (CSIC) and Universidad de Salamanca SpainThe mevalonate pathway plays an important role in breast cancer and other tumor types. However, many issues remain obscure as yet regarding its mechanism of regulation and action. In the present study, we report that the expression of mevalonate pathway enzymes is mediated by the RHO guanosine nucleotide exchange factors VAV2 and VAV3 in a RAC1‐ and sterol regulatory element‐binding factor (SREBF)‐dependent manner in breast cancer cells. Furthermore, in vivo tumorigenesis experiments indicated that the two most upstream steps of this metabolic pathway [3‐hydroxy‐3‐methylglutaryl‐coenzyme A synthase 1 (HMGCS1) and 3‐hydroxy‐3‐methylglutaryl‐coenzyme A reductase (HMGCR)] are important for primary tumorigenesis, angiogenesis, and cell survival in breast cancer cells. HMGCR, but not HMGCS1, is also important for the extravasation and subsequent fitness of breast cancer cells in the lung parenchyma. Genome‐wide expression analyses revealed that HMGCR influences the expression of gene signatures linked to proliferation, metabolism, and immune responses. The HMGCR‐regulated gene signature predicts long‐term tumor recurrence but not metastasis in cohorts of nonsegregated and chemotherapy‐resistant breast cancer patients. These results reveal a hitherto unknown, VAV‐catalysis‐dependent mechanism involved in the regulation of the mevalonate pathway in breast cancer cells. They also identify specific mevalonate‐pathway‐dependent processes that contribute to the malignant features of breast cancer cells.https://doi.org/10.1002/1878-0261.13716cholesterolguanosine nucleotide exchange factorsoncogenic signalingRAC1RHO GTPasessterol regulatory element‐binding protein |
| spellingShingle | Javier Conde Isabel Fernández‐Pisonero L. Francisco Lorenzo‐Martín Rocío García‐Gómez Berta Casar Piero Crespo Xosé R. Bustelo The mevalonate pathway contributes to breast primary tumorigenesis and lung metastasis Molecular Oncology cholesterol guanosine nucleotide exchange factors oncogenic signaling RAC1 RHO GTPases sterol regulatory element‐binding protein |
| title | The mevalonate pathway contributes to breast primary tumorigenesis and lung metastasis |
| title_full | The mevalonate pathway contributes to breast primary tumorigenesis and lung metastasis |
| title_fullStr | The mevalonate pathway contributes to breast primary tumorigenesis and lung metastasis |
| title_full_unstemmed | The mevalonate pathway contributes to breast primary tumorigenesis and lung metastasis |
| title_short | The mevalonate pathway contributes to breast primary tumorigenesis and lung metastasis |
| title_sort | mevalonate pathway contributes to breast primary tumorigenesis and lung metastasis |
| topic | cholesterol guanosine nucleotide exchange factors oncogenic signaling RAC1 RHO GTPases sterol regulatory element‐binding protein |
| url | https://doi.org/10.1002/1878-0261.13716 |
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