Halting ErbB-2 isoforms retrograde transport to the nucleus as a new theragnostic approach for triple-negative breast cancer
Abstract Triple-negative breast cancer (TNBC) is clinically defined by the absence of estrogen and progesterone receptors and the lack of membrane overexpression or gene amplification of receptor tyrosine kinase ErbB-2/HER2. Due to TNBC heterogeneity, clinical biomarkers and targeted therapies for t...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2022-05-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-022-04855-0 |
| _version_ | 1797362874674315264 |
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| author | Santiago Madera Franco Izzo María F. Chervo Agustina Dupont Violeta A. Chiauzzi Sofia Bruni Ezequiel Petrillo Sharon S. Merin Mara De Martino Diego Montero Claudio Levit Gabriel Lebersztein Fabiana Anfuso Agustina Roldán Deamicis María F. Mercogliano Cecilia J. Proietti Roxana Schillaci Patricia V. Elizalde Rosalía I. Cordo Russo |
| author_facet | Santiago Madera Franco Izzo María F. Chervo Agustina Dupont Violeta A. Chiauzzi Sofia Bruni Ezequiel Petrillo Sharon S. Merin Mara De Martino Diego Montero Claudio Levit Gabriel Lebersztein Fabiana Anfuso Agustina Roldán Deamicis María F. Mercogliano Cecilia J. Proietti Roxana Schillaci Patricia V. Elizalde Rosalía I. Cordo Russo |
| author_sort | Santiago Madera |
| collection | DOAJ |
| description | Abstract Triple-negative breast cancer (TNBC) is clinically defined by the absence of estrogen and progesterone receptors and the lack of membrane overexpression or gene amplification of receptor tyrosine kinase ErbB-2/HER2. Due to TNBC heterogeneity, clinical biomarkers and targeted therapies for this disease remain elusive. We demonstrated that ErbB-2 is localized in the nucleus (NErbB-2) of TNBC cells and primary tumors, from where it drives growth. We also discovered that TNBC expresses both wild-type ErbB-2 (WTErbB-2) and alternative ErbB-2 isoform c (ErbB-2c). Here, we revealed that the inhibitors of the retrograde transport Retro-2 and its cyclic derivative Retro-2.1 evict both WTErbB-2 and ErbB-2c from the nucleus of BC cells and tumors. Using BC cells from several molecular subtypes, as well as normal breast cells, we demonstrated that Retro-2 specifically blocks proliferation of BC cells expressing NErbB-2. Importantly, Retro-2 eviction of both ErbB-2 isoforms from the nucleus resulted in a striking growth abrogation in multiple TNBC preclinical models, including tumor explants and xenografts. Our mechanistic studies in TNBC cells revealed that Retro-2 induces a differential accumulation of WTErbB-2 at the early endosomes and the plasma membrane, and of ErbB-2c at the Golgi, shedding new light both on Retro-2 action on endogenous protein cargoes undergoing retrograde transport, and on the biology of ErbB-2 splicing variants. In addition, we revealed that the presence of a functional signal peptide and a nuclear export signal (NES), both located at the N-terminus of WTErbB-2, and absent in ErbB-2c, accounts for the differential subcellular distribution of ErbB-2 isoforms upon Retro-2 treatment. Our present discoveries provide evidence for the rational repurposing of Retro-2 as a novel therapeutic agent for TNBC. |
| first_indexed | 2024-03-08T16:12:42Z |
| format | Article |
| id | doaj.art-c5cf687b8b084672a59b0ffb44e8ef9e |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-03-08T16:12:42Z |
| publishDate | 2022-05-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-c5cf687b8b084672a59b0ffb44e8ef9e2024-01-07T12:49:20ZengNature Publishing GroupCell Death and Disease2041-48892022-05-0113511410.1038/s41419-022-04855-0Halting ErbB-2 isoforms retrograde transport to the nucleus as a new theragnostic approach for triple-negative breast cancerSantiago Madera0Franco Izzo1María F. Chervo2Agustina Dupont3Violeta A. Chiauzzi4Sofia Bruni5Ezequiel Petrillo6Sharon S. Merin7Mara De Martino8Diego Montero9Claudio Levit10Gabriel Lebersztein11Fabiana Anfuso12Agustina Roldán Deamicis13María F. Mercogliano14Cecilia J. Proietti15Roxana Schillaci16Patricia V. Elizalde17Rosalía I. Cordo Russo18Laboratory of Molecular Mechanisms of Carcinogenesis and Molecular Endocrinology, Instituto de Biología y Medicina Experimental (IBYME), CONICETNew York Genome CenterLaboratory of Molecular Mechanisms of Carcinogenesis and Molecular Endocrinology, Instituto de Biología y Medicina Experimental (IBYME), CONICETLaboratory of Molecular Mechanisms of Carcinogenesis and Molecular Endocrinology, Instituto de Biología y Medicina Experimental (IBYME), CONICETLaboratory of Molecular Mechanisms of Carcinogenesis and Molecular Endocrinology, Instituto de Biología y Medicina Experimental (IBYME), CONICETLaboratory of Molecular Mechanisms of Carcinogenesis and Molecular Endocrinology, Instituto de Biología y Medicina Experimental (IBYME), CONICETUniversidad de Buenos Aires (UBA), Facultad de Ciencias Exactas y Naturales, Departamento de Fisiología, Biología Molecular y Celular and CONICET-UBA, Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE)Laboratory of Molecular Mechanisms of Carcinogenesis and Molecular Endocrinology, Instituto de Biología y Medicina Experimental (IBYME), CONICETDepartment of Radiation Oncology, Weill Cornell MedicineLaboratory of Molecular Mechanisms of Carcinogenesis and Molecular Endocrinology, Instituto de Biología y Medicina Experimental (IBYME), CONICETServicio de Ginecología, Sanatorio Sagrado CorazónServicio de Ginecología, Sanatorio Sagrado CorazónServicio de Ginecología, Sanatorio Sagrado CorazónLaboratory of Molecular Mechanisms of Carcinogenesis and Molecular Endocrinology, Instituto de Biología y Medicina Experimental (IBYME), CONICETLaboratory of Molecular Mechanisms of Carcinogenesis and Molecular Endocrinology, Instituto de Biología y Medicina Experimental (IBYME), CONICETLaboratory of Molecular Mechanisms of Carcinogenesis and Molecular Endocrinology, Instituto de Biología y Medicina Experimental (IBYME), CONICETLaboratory of Molecular Mechanisms of Carcinogenesis and Molecular Endocrinology, Instituto de Biología y Medicina Experimental (IBYME), CONICETLaboratory of Molecular Mechanisms of Carcinogenesis and Molecular Endocrinology, Instituto de Biología y Medicina Experimental (IBYME), CONICETLaboratory of Molecular Mechanisms of Carcinogenesis and Molecular Endocrinology, Instituto de Biología y Medicina Experimental (IBYME), CONICETAbstract Triple-negative breast cancer (TNBC) is clinically defined by the absence of estrogen and progesterone receptors and the lack of membrane overexpression or gene amplification of receptor tyrosine kinase ErbB-2/HER2. Due to TNBC heterogeneity, clinical biomarkers and targeted therapies for this disease remain elusive. We demonstrated that ErbB-2 is localized in the nucleus (NErbB-2) of TNBC cells and primary tumors, from where it drives growth. We also discovered that TNBC expresses both wild-type ErbB-2 (WTErbB-2) and alternative ErbB-2 isoform c (ErbB-2c). Here, we revealed that the inhibitors of the retrograde transport Retro-2 and its cyclic derivative Retro-2.1 evict both WTErbB-2 and ErbB-2c from the nucleus of BC cells and tumors. Using BC cells from several molecular subtypes, as well as normal breast cells, we demonstrated that Retro-2 specifically blocks proliferation of BC cells expressing NErbB-2. Importantly, Retro-2 eviction of both ErbB-2 isoforms from the nucleus resulted in a striking growth abrogation in multiple TNBC preclinical models, including tumor explants and xenografts. Our mechanistic studies in TNBC cells revealed that Retro-2 induces a differential accumulation of WTErbB-2 at the early endosomes and the plasma membrane, and of ErbB-2c at the Golgi, shedding new light both on Retro-2 action on endogenous protein cargoes undergoing retrograde transport, and on the biology of ErbB-2 splicing variants. In addition, we revealed that the presence of a functional signal peptide and a nuclear export signal (NES), both located at the N-terminus of WTErbB-2, and absent in ErbB-2c, accounts for the differential subcellular distribution of ErbB-2 isoforms upon Retro-2 treatment. Our present discoveries provide evidence for the rational repurposing of Retro-2 as a novel therapeutic agent for TNBC.https://doi.org/10.1038/s41419-022-04855-0 |
| spellingShingle | Santiago Madera Franco Izzo María F. Chervo Agustina Dupont Violeta A. Chiauzzi Sofia Bruni Ezequiel Petrillo Sharon S. Merin Mara De Martino Diego Montero Claudio Levit Gabriel Lebersztein Fabiana Anfuso Agustina Roldán Deamicis María F. Mercogliano Cecilia J. Proietti Roxana Schillaci Patricia V. Elizalde Rosalía I. Cordo Russo Halting ErbB-2 isoforms retrograde transport to the nucleus as a new theragnostic approach for triple-negative breast cancer Cell Death and Disease |
| title | Halting ErbB-2 isoforms retrograde transport to the nucleus as a new theragnostic approach for triple-negative breast cancer |
| title_full | Halting ErbB-2 isoforms retrograde transport to the nucleus as a new theragnostic approach for triple-negative breast cancer |
| title_fullStr | Halting ErbB-2 isoforms retrograde transport to the nucleus as a new theragnostic approach for triple-negative breast cancer |
| title_full_unstemmed | Halting ErbB-2 isoforms retrograde transport to the nucleus as a new theragnostic approach for triple-negative breast cancer |
| title_short | Halting ErbB-2 isoforms retrograde transport to the nucleus as a new theragnostic approach for triple-negative breast cancer |
| title_sort | halting erbb 2 isoforms retrograde transport to the nucleus as a new theragnostic approach for triple negative breast cancer |
| url | https://doi.org/10.1038/s41419-022-04855-0 |
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