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Sanz-Moreno, A. ; Palomeras, S.* ; Pedersen, K.* ; Morancho, B.* ; Pascual, T.* ; Galvan, P.* ; Benitez, S.* ; Gomez-Miragaya, J.* ; Ciscar, M.* ; Jimenez, M.* ; Pernas, S.* ; Petit, A.* ; Soler-Monso, M.T.* ; Vinas, G.* ; Alsaleem, M.* ; Rakha, E.A.* ; Green, A.R.* ; Santamaria, P.G.* ; Mulder, C.* ; Lemeer, S.* ; Arribas, J.* ; Prat, A.* ; Puig, T.* ; Gonzalez-Suarez, E.*

RANK signaling increases after anti-HER2 therapy contributing to the emergence of resistance in HER2-positive breast cancer.

Breast Cancer Res. 23:42 (2021)
Verlagsversion Forschungsdaten DOI
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
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-kappa B 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-kappa B 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-kappa B 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-kappa B activation. Whether HER2-positive breast cancer patients with tumoral RANK expression might benefit from dual HER2 and RANK inhibition therapy remains to be elucidated.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Breast Cancer ; Her2 ; Lapatinib ; Nf-κ ; B ; Rank ; Rankl ; Resistance ; Trastuzumab
ISSN (print) / ISBN 1465-5411
e-ISSN 1465-542X
Quellenangaben Band: 23, Heft: 1, Seiten: , Artikelnummer: 42 Supplement: ,
Verlag BioMed Central
Verlagsort Campus, 4 Crinan St, London N1 9xw, England
Begutachtungsstatus Peer reviewed
Förderungen Save the Mama
Spanish Instituto de Salud Carlos III (ISCIII)
La Marato de TV3
Catalan Government
European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme ERC Consolidator grant
Pas a Pas
Data to Early Diagnosis and Precision Medicine strand of the UK Government's Industrial Strategy Challenge Fund (UKRI)
Breast Cancer Research Foundation
Banco Bilbao Vizcaya Argentaria (BBVA) Foundation
Susan Komen Foundation
PERIS fellowship (Departament de Salut, Generalitat de Catalunya)
Asociacion Espanola Contra el Cancer
Spanish Ministerio de Ciencia, Innovacion y Universidades, Agencia Estatal de Investigacion (AEI)