HEREGULIN-TRIGGERED BREAST CANCER CELL MIGRATION IS PREVENTED BY ANTI-HER-2 THERAPIES

MONDACA, JM; CASTRO GUIJARRO, AC; UZAIR, ID; VANDERHOEVEN, F; FLAMINI, MI; SANCHEZ AM,

Palma

Workshop; 2nd International Workshop on Translational Cancer Research; 2021

Background and Aims:Heregulin (HRG) signaling has been implicated in the development of an aggressive phenotype in breastcancer (BC) cells, and HER2 overexpression has been associated with a worse prognosis in BC patients.Nevertheless, the molecular mechanisms through which HRG affects the efficiency of anti-HER2 therapiessuch as trastuzumab (Tz) and trastuzumabemtansine (T-DM1) are currently unknown. In the presentstudy, we evaluate the molecular action of HRG toward fundamental scaffold proteins and several kinasesin the signal transduction pathways triggered via HER2/HER3, which integrate precise and sequential stepsto promote changes in cell morphology to impulse BC cell migration. In addition, we evaluate theeffectiveness of Tz and T-DM1 on the control of key proteins involved in BC cell motilityMethods:We used human BC cell line BT-474 (HER2+) as experimental model. For the development of the project,we used various molecular assays such as cell viability, migration, western blots, immunofluorescence,immunoprecipitations, specific Transfections/Silencing and statistical analysis with ANOVA and Tukey-Kramer tests.Results:We show that HRG induces actin cytoskeleton reorganization and focal adhesion complex formation, andpromotes actin nucleation in BT-474 BC cells. This signaling is triggered by HER2/HER3 to c-Src, FAK andpaxillin. When paxillin is phosphorylated, it recruits PAK1, which then phosphorylates cortactin. In parallel,paxillin signals to N-WASP, and both signalings regulate Arp2/3 complex, leading to the localreorganization of actin fibers.Conclusions:Our findings reveal an original mechanism by which HRG increases BC cell motility, and show that thelatter can be abolished by Tz and T-DM1 treatments. These results provide evidence for the molecularmechanisms involved in cell motility and drug resistance. They will be useful to develop new and morespecific therapeutic schemes that interfere with the progression and metastasis of HER2+ BC.