Abstract
BackgroundAround 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.MethodsRANK 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.ResultsRANK 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.ConclusionsOur 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.
Highlights
Around 15–20% of primary breast cancers are characterized by human epidermal growth factor receptor 2 (HER2) protein overexpression and/or HER2 gene amplification
Our results indicate that ErbB signaling is required for RANK/Receptor activator of nuclear factor kappa-Β ligand (RANKL)-driven activation of ERK in several HER2-positive cell lines
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 Nuclear factor kappa B (NF-κB) activation
Summary
Around 15–20% of primary breast cancers are characterized by HER2 protein overexpression and/or HER2 gene amplification. The human epidermal growth factor receptor 2 (HER2), known as ErbB2 or Neu, is a tyrosine kinase receptor protein encoded by the ERBB2 (HER2) gene [1]. HER2 is a member of the epidermal growth factor (EGF) receptor family along with EGFR/HER1, ERBB3/HER3, and ERBB4/HER4. 15–20% of primary breast cancers show HER2 protein overexpression and/or HER2 gene amplification [2], which is associated with poor prognosis. The development of humanized monoclonal antibodies binding the extracellular domain of HER2 (e.g., trastuzumab, pertuzumab), EGFR-HER2 small molecule kinase inhibitors (e.g., lapatinib, neratinib, or tucatinib), and antibody-drug conjugates (e.g., T-DM1 or DS-8201) has revolutionized HER2positive breast cancer treatment [3]. Elucidating the mechanisms of resistance to antiHER2 drugs is pivotal to further improve patients’ survival outcomes
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