2026-05-20T19:10:30Zhttps://repisalud.isciii.es/rest/oai/request

oai:repisalud.isciii.es:20.500.12105/251762025-12-18T12:59:51Zcom_20.500.12105_2327com_20.500.12105_2290col_20.500.12105_16991

00925njm 22002777a 4500 dc Sanz-Moreno, Adrián author Palomeras, Sonia author Pedersen, Kim author Morancho, Beatriz author Pascual, Tomas author Galván, Patricia author Benítez, Sandra author Gomez-Miragaya, Jorge author Ciscar, Marina author Jimenez, Maria author Pernas, Sonia author Petit, Anna author Soler-Monsó, María Teresa author Viñas, Gemma author Alsaleem, Mansour author Rakha, Emad A author Green, Andrew R author Santamaria, Patricia G author Mulder, Celine author Lemeer, Simone author Arribas, Joaquin author Prat, Aleix author Puig, Teresa author Gonzalez-Suarez, Eva author Sanz-Moreno, Adrián author Palomeras, Sonia author Pedersen, Kim author Morancho, Beatriz author Pascual, Tomas author Galván, Patricia author Benítez, Sandra author Gomez-Miragaya, Jorge author Ciscar, Marina author Jimenez, Maria author Pernas, Sonia author Petit, Anna author Soler-Monsó, María Teresa author Viñas, Gemma author Alsaleem, Mansour author Rakha, Emad A author Green, Andrew R author Santamaria, Patricia G author Mulder, Celine author Lemeer, Simone author Arribas, Joaquin author Prat, Aleix author Puig, Teresa author Gonzalez-Suarez, Eva author 2021-03-30 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. 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. 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. 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. Breast Cancer Res . 2021 Mar 30;23(1):42. Breast Cancer Research 33785053 https://hdl.handle.net/20.500.12105/25176 Breast cancer HER2 Lapatinib NF-κB RANK RANKL Resistance Trastuzumab RANK signaling increases after anti-HER2 therapy contributing to the emergence of resistance in HER2-positive breast cancer.