THE IMPORTANCE OF HYALURONAN IN BREAST CANCER PROGRESSION AND RESISTANCE TO ERBB-2 THERAPY

SANTIAGO MADERA ; M FLORENCIA CHERBO; VIOLETA A. CHIAUZZI ; ALANIZ LAURA; CECILIA J. PROIETTI ; ROXANNA SCHILLACI ; EDUARDO H. CHARREAU ; PATRICIA V. ELIZALDE ; ROSALÍA I. CORDO RUSSO

Ciudad de Buenos Aires

Congreso; REUNIÓN CONJUNTA DE SOCIEDADES DE BIOCIENCIAS; 2017

SAIC; SAIB; SAI; SAA; SAB; SAFE; SAFIS; SAH; SAP

Hyaluronan (HA), one of the main components of the tumor microenvironment, promotes oncogenic signals, activates migration and metastasis and induces resistance to antineoplastic agents through its interaction with its receptor CD44. Accumulation of HA is associated with poor prognosis and resistance to 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. In addition to its membrane function, ErbB-2 migrates to the nucleus (NErbB-2) where it acts as a transcription factor (FT) or coactivator of TF, modulating proliferation, metastasis and resistance to anti-ErbB-2 therapies in BC. Although crosstalk between ErbB-2 and HA/CD44 pathways has been report, how the molecular interactions between said pathways mediate resistance to TZ remains poorly known. Here, we found that HA stimuli induced nuclear translocation of ErbB-2 in T47D BC cells. JIMT1 BC cell line constitutes a classical model of resistance to TZ. In this cell line, which expresses high levels of HA and NErbB-2, constitutive levels of nuclear CD44 were increased when stimulated with exogenous HA. Treatment with the chemical inhibitor of HA synthesis 4-methylumbelliferone (4MU) decreased not only HA levels but also NErbB-2 in JIMT1 cells. We also explored the role of HA synthesis inhibition in cell proliferation and migration: Treatment with 4MU impaired proliferation of JIMT1 cells similarly to the one observed when ErbB-2 was excluded from the nucleus via transfection with hErbB-2ΔNLS mutant. Even more, wound-healing assays showed that 4MU inhibited JIMT1 cell migration. In summary, we reveal that HA induces ErbB-2 and CD44 nuclear translocation, thus leading to the assembly of transcriptional complexes that would induce proliferation and migration of BC cells resistant to TZ. Our findings also highlight blockade of HA presence with 4MU as a novel therapeutic strategy in TZ-resistant BC.