Abstract
Abstract The tumor microenvironment component hyaluronan (HA) induces tumor progression through the interaction with its cell surface receptor CD44. Accumulation of HA is associated with poor prognosis and resistance to the anti-ErbB-2 agent trastuzumab (TZ) in breast cancer (BC). ErbB-2 receptor is overexpressed in 15-20% of BC patients (ErbB-2+) and constitutes an important therapeutic target. Despite the clinical efficiency of therapies targeting ErbB-2, resistance to these drugs remains a major issue. In addition to its membrane function, ErbB-2 migrates to the nucleus (NErbB-2) where it acts as a transcription factor (TF) or as a coactivator of TF, modulating proliferation, metastasis, and resistance to anti-ErbB-2 therapies in BC. CD44 has also been found in the nucleus (NCD44). Although crosstalk between HA/CD44 and ErbB-2 pathways has been reported, how their molecular interactions mediate TZ resistance remains poorly known. Our in silico studies showed that TZ-resistant cells express higher CD44 levels than TZ-sensitive ones. We previously reported that stimulation with the ErbBs ligand heregulin (HRG) induces NErbB-2 translocation, acquired-TZ resistance and proliferation in the TZ-sensitive SK-BR-3 cell line. Here, we found that HRG also increased CD44 mRNA expression in SK-BR-3 cells. Then, we explored the role of HA in modulating CD44 and ErbB-2 nuclear localization in BC cells. Immunofluorescence and confocal microscopy studies showed that stimulation with exogenous HA induced nuclear translocation of ErbB-2 in T47D cells. Interestingly, we found constitutive presence of CD44 and ErbB-2 protein in nuclear lysates of JIMT-1 cells, a de novo TZ-resistant BC model. HA stimuli further enhanced this nuclear localization. Contrarily, treatment with the chemical inhibitor of HA synthesis 4-methylumbelliferone (4MU) decreased not only HA levels but also NErbB-2 in JIMT-1 cells. Furthermore, 4MU inhibited the proliferation of two TZ-resistant cell lines, JIMT-1 and MDA-MB-453, in a dose-dependent manner. 4MU also inhibited HRG-induced proliferation in SK-BR-3 cells. Even more, wound-healing assays showed that 4MU inhibited migration of JIMT-1 cells. This inhibition was similar to the one observed when ErbB-2 was excluded from the nucleus via transfection with the hErbB-2ΔNLS mutant. In summary, we reveal that HA induces CD44 and ErbB-2 nuclear localization in BC cells, suggesting a novel crosstalk between HA/CD44 and ErbB-2 pathways. These findings also highlight the blockade of HA synthesis with 4MU as a novel therapeutic strategy in TZ-resistant BC. Citation Format: Santiago Madera, Valentina C. Bulian, Sharon S. Merin, María F. Mercogliano, Roxana Schillaci, Rosalia I. Cordo Russo. Exploring a novel crosstalk between hyluronan/CD44 and ErbB-2 pathways in resistance to ErbB-2-targeted therapies in breast cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3633.
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