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http://hdl.handle.net/2445/176249
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DC Field | Value | Language |
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dc.contributor.author | Sanz Moreno, Adrián | - |
dc.contributor.author | Palomeras, Sonia | - |
dc.contributor.author | Pedersen, Kim | - |
dc.contributor.author | Morancho, Beatriz | - |
dc.contributor.author | Pascual, Tomás | - |
dc.contributor.author | Galván, Patricia | - |
dc.contributor.author | Benítez, Sandra | - |
dc.contributor.author | Gómez Miragaya, Jorge | - |
dc.contributor.author | Ciscar, Marina | - |
dc.contributor.author | Jimenez, Maria | - |
dc.contributor.author | Pernas, Sònia | - |
dc.contributor.author | Petit, Anna | - |
dc.contributor.author | Soler, María Teresa | - |
dc.contributor.author | Viñas, Gemma | - |
dc.contributor.author | Alsaleem, Mansour | - |
dc.contributor.author | Rakha, Emad A. | - |
dc.contributor.author | Green, Andrew R. | - |
dc.contributor.author | Santamaria, Patricia G. | - |
dc.contributor.author | Mulder, Celine | - |
dc.contributor.author | Lemeer, Simone | - |
dc.contributor.author | Arribas, Joaquín V. (Vicente) | - |
dc.contributor.author | Prat Aparicio, Aleix | - |
dc.contributor.author | Puig, Teresa | - |
dc.contributor.author | González Suárez, Eva | - |
dc.date.accessioned | 2021-04-16T10:51:41Z | - |
dc.date.available | 2021-04-16T10:51:41Z | - |
dc.date.issued | 2021-03-30 | - |
dc.identifier.uri | http://hdl.handle.net/2445/176249 | - |
dc.description.abstract | Background: Around 15-20% of primary breast cancers are characterized by HER2 protein overexpression and/or HER2 gene amplification. Despite the successful development of anti-HER2 drugs, intrinsic and acquired resistance represents a major hurdle. This study was performed to analyze the RANK pathway contribution in HER2-positive breast cancer and anti-HER2 therapy resistance. Methods: RANK and RANKL protein expression was assessed in samples from HER2-positive breast cancer patients resistant to anti-HER2 therapy and treatment-naive patients. RANK and RANKL gene expression was analyzed in paired samples from patients treated with neoadjuvant dual HER2-blockade (lapatinib and trastuzumab) from the SOLTI-1114 PAMELA trial. Additionally, HER2-positive breast cancer cell lines were used to modulate RANK expression and analyze in vitro the contribution of RANK signaling to anti-HER2 resistance and downstream signaling. Results: RANK and RANKL proteins are more frequently detected in HER2-positive tumors that have acquired resistance to anti-HER2 therapies than in treatment-naive ones. RANK (but not RANKL) gene expression increased after dual anti-HER2 neoadjuvant therapy in the cohort from the SOLTI-1114 PAMELA trial. Results in HER2-positive breast cancer cell lines recapitulate the clinical observations, with increased RANK expression observed after short-term treatment with the HER2 inhibitor lapatinib or dual anti-HER2 therapy and in lapatinib-resistant cells. After RANKL stimulation, lapatinib-resistant cells show increased NF-κB activation compared to their sensitive counterparts, confirming the enhanced functionality of the RANK pathway in anti-HER2-resistant breast cancer. Overactivation of the RANK signaling pathway enhances ERK and NF-κB signaling and increases lapatinib resistance in different HER2-positive breast cancer cell lines, whereas RANK loss sensitizes lapatinib-resistant cells to the drug. Our results indicate that ErbB signaling is required for RANK/RANKL-driven activation of ERK in several HER2-positive cell lines. In contrast, lapatinib is not able to counteract the NF-κB activation elicited after RANKL treatment in RANK-overexpressing cells. Finally, we show that RANK binds to HER2 in breast cancer cells and that enhanced RANK pathway activation alters HER2 phosphorylation status. Conclusions: Our data support a physical and functional link between RANK and HER2 signaling in breast cancer and demonstrate that increased RANK signaling may contribute to the development of lapatinib resistance through NF-κB activation. Whether HER2-positive breast cancer patients with tumoral RANK expression might benefit from dual HER2 and RANK inhibition therapy remains to be elucidated. | - |
dc.format.extent | 18 p. | - |
dc.format.mimetype | application/pdf | - |
dc.language.iso | eng | - |
dc.publisher | Springer Nature | - |
dc.relation.isformatof | Reproducció del document publicat a: https://doi.org/10.1186/s13058-021-01390-2 | - |
dc.relation.ispartof | Breast Cancer Research, 2021, vol. 23 | - |
dc.relation.uri | https://doi.org/10.1186/s13058-021-01390-2 | - |
dc.rights | cc by (c) Sanz Moreno et al., 2021 | - |
dc.rights.uri | http://creativecommons.org/licenses/by/3.0/es/ | * |
dc.source | Articles publicats en revistes (Medicina) | - |
dc.subject.classification | Càncer de mama | - |
dc.subject.classification | Resistència als medicaments | - |
dc.subject.other | Breast cancer | - |
dc.subject.other | Drug resistance | - |
dc.title | RANK signaling increases after anti-HER2 therapy contributing to the emergence of resistance in HER2-positive breast cancer | - |
dc.type | info:eu-repo/semantics/article | - |
dc.type | info:eu-repo/semantics/publishedVersion | - |
dc.date.updated | 2021-04-16T09:20:40Z | - |
dc.relation.projectID | info:eu-repo/grantAgreement/EC/H2020/682935/EU//PLEIO-RANK | - |
dc.rights.accessRights | info:eu-repo/semantics/openAccess | - |
dc.identifier.pmid | 33785053 | - |
Appears in Collections: | Articles publicats en revistes (Medicina) Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer) Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL)) |
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File | Description | Size | Format | |
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s13058-021-01390-2.pdf | 2.13 MB | Adobe PDF | View/Open |
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