The importance of hyaluronan in breast cancer progression and resistance to anti-ErbB-2 therapy.

MADERA S; CHERVO MF; CHIAUZZI VA; ALANIZ L; PROIETTI CJ; SCHILLACI R; CHARREAU EH; ELIZALDE PV; CORDO RUSSO RI

Buenos Aires

Congreso; LXII REUNIÓN ANUAL DE LA SOCIEDAD ARGENTINA DE INVESTIGACIÓN CLÍNICA (SAIC); 2017

Sociedad Argentina de Investigaciones Clinicas

Hyaluronan (HA), one of the main components of the tumor microenvironment,promotes oncogenic signals, activates migrationand metastasis and induces resistance to antineoplastic agentsthrough its interaction with its receptor CD44. Accumulation of HAis associated with poor prognosis and resistance to anti-ErbB-2agent trastuzumab (TZ) in breast cancer (BC). ErbB-2 receptoris overexpressed in 15-20% of BC patients (ErbB-2+) and constitutesan important therapeutic target. In addition to its membranefunction, ErbB-2 migrates to the nucleus (NErbB-2) where it actsas a transcription factor (FT) or coactivator of TF, modulating proliferation,metastasis and resistance to anti-ErbB-2 therapiesin BC. Although crosstalk between ErbB-2 and HA/CD44 pathwayshas been report, how the molecular interactions betweensaid pathways mediate resistance to TZ remains poorly known.Here, we found that HA stimuli induced nuclear translocation ofErbB-2 in T47D BC cells. JIMT1 BC cell line constitutes a classicalmodel of resistance to TZ. In this cell line, which expresses highlevels of HA and NErbB-2, constitutive levels of nuclear CD44 wereincreased when stimulated with exogenous HA. Treatment with thechemical inhibitor of HA synthesis 4-methylumbelliferone (4MU) decreasednot only HA levels but also NErbB-2 in JIMT1 cells.We also explored the role of HA synthesis inhibition in cellproliferation and migration: Treatment with 4MU impairedproliferation of JIMT1 cells similarly to the one observedwhen ErbB-2 was excluded from the nucleus via transfectionwith hErbB-2ΔNLS mutant. Even more, wound-healingassays showed that 4MU inhibited JIMT1 cell migration.In summary, we reveal that HA induces ErbB-2 and CD44 nucleartranslocation, thus leading to the assembly of transcriptional complexesthat would induce proliferation and migration of BC cells resistantto TZ. Our findings also highlight blockade of HA presencewith 4MU as a novel therapeutic strategy in TZ-resistant BC.