Decephering the role of hyaluronan in resistance to ErbB-2-targeted therapies in breast cancer.

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

Buenos Aires

Simposio; Alexander von Humboldt Colloquium; 2018

Alexander von Humboldt Foundation

Approximately 15?20% of breast cancers (BC) show either membrane overexpression of ErbB-2, a member of the ErbBs family of receptor tyrosine kinases, or ERBB2 gene amplification. Until the development of ErbB-2-targeted therapies, this BC subtype, called ErbB-2-positive, was associated with increased metastatic potential and poor prognosis. Although these therapies have significantly improved overall survival and cure rates, resistance to available drugs is still a major clinical issue. In addition to its membrane function, ErbB-2 migrates to the nucleus (NErbB-2) where it acts as a transcription factor (FT) or, according to our previous findings, as a coactivator of TF, to modulate proliferation, metastasis and resistance to anti-ErbB-2 therapies in BC. Hyaluronan (HA), a linear glycosaminoglycan, is a prominent component of the extracellular matrix within the tumor microenvironment. Accumulation of HA is associated with poor prognosis and resistance to anti-ErbB-2 agent trastuzumab (TZ) in BC. Through its interaction with the CD44 receptor, a type I transmembrane glycoprotein, HA promotes oncogenic signals, activates migration and metastasis, and induces resistance to antineoplastic agents. A novel aspect of CD44 biology was the discovery of its ability to migrate to the nuclear compartment and to activate the transcription of genes. Although crosstalk between ErbB-2 and HA/CD44 pathways has been reported, how the molecular interactions between said pathways mediate resistance to TZ remains unknown. Here, we explored the role of HA on modulation of CD44 and ErbB-2 nuclear localization and resistance to anti-ErbB-2 therapies. We found that HA stimuli induced nuclear translocation of ErbB-2 in T47D BC cells. JIMT-1 cell line constitutes a classical model of resistance to TZ, which basally express high levels of HA and of NErbB-2. In this cell line, we also found constitutive levels of nuclear CD44. Moreover, treatment with exogenous HA further increased both ErbB-2 and CD44 nuclear translocation. Treatment with the chemical inhibitor of HA synthesis 4-methylumbelliferone (4MU) decreased not only HA levels but also NErbB-2 presence in JIMT1 cells. We also explored the role of HA synthesis inhibition in cell proliferation and migration of TZ-resistant BC cells. We found that treatment with 4MU impaired proliferation of JIMT1 cells similarly to the one observed when ErbB-2 was excluded from the nucleus via transfection with the 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 the blockade of HA presence with 4MU as a novel therapeutic strategy in TZ-resistant BC.