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

MADERA SANTIAGO; CHERVO FLORENCIA; CHIAUZZI VIOLETA A.; ALANIZ LAURA D.; PROIETTI CECILIA J.; SCHILLACI ROXANA; CHARREAU EDUARDO H.; ELIZALDE PATRICIA V.; CORDO RUSSO PATRICIA V.

Congreso; Reunión Conjunta de Sociedades de Biociencias- LXII Reunión Anual de la Sociedad Argentina de Investigación Clínica (SAIC); 2017

Hyaluronan(HA), one of the main components of the tumor microenvironment,promotesoncogenic signals, activates migrationand metastasisand induces resistance to antineoplastic agentsthrough itsinteraction with its receptor CD44. Accumulation of HAis associatedwith poor prognosis and resistance to anti-ErbB-2agenttrastuzumab (TZ) in breast cancer (BC). ErbB-2 receptoris overexpressedin 15-20% of BC patients (ErbB-2+) and constitutesan importanttherapeutic target. In addition to its membranefunction,ErbB-2 migrates to the nucleus (NErbB-2) where it actsas atranscription factor (FT) or coactivator of TF, modulating proliferation,metastasis andresistance to anti-ErbB-2 therapiesin BC.Although crosstalk between ErbB-2 and HA/CD44 pathwayshas beenreport, how the molecular interactions betweensaid pathwaysmediate resistance to TZ remains poorly known.Here, we foundthat HA stimuli induced nuclear translocation ofErbB-2 in T47DBC cells. JIMT1 BC cell line constitutes a classicalmodel ofresistance to TZ. In this cell line, which expresses highlevels of HAand NErbB-2, constitutive levels of nuclear CD44 wereincreased whenstimulated with exogenous HA. Treatment with thechemicalinhibitor of HA synthesis 4-methylumbelliferone (4MU) decreasednot only HAlevels but also NErbB-2 in JIMT1 cells.We alsoexplored the role of HA synthesis inhibition in cellproliferationand migration: Treatment with 4MU impairedproliferationof JIMT1 cells similarly to the one observedwhen ErbB-2was excluded from the nucleus via transfectionwith hErbB-2ΔNLS mutant.Even more, wound-healingassays showedthat 4MU inhibited JIMT1 cell migration.In summary, wereveal that HA induces ErbB-2 and CD44 nucleartranslocation,thus leading to the assembly of transcriptional complexesthat wouldinduce proliferation and migration of BC cells resistantto TZ. Ourfindings also highlight blockade of HA presencewith 4MU as anovel therapeutic strategy in TZ-resistant BC.Keywords:breast cancer, hyaluronan, tumor microenvironment,extracellularmatrix, nuclear ErbB-2.