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

JOSELINA M. MONDACA; ANA C. CASTRO GUIJARRO; IVONNE D. UZAIR; FIORELLA VANDERHOEVEN; MARINA I. FLAMINI; ANGEL M. SANCHEZ

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 breast cancer (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 therapies such as trastuzumab (Tz) and trastuzumab emtansine (T-DM1) are currently unknown. In the present study, we evaluate the molecular action of HRG toward fundamental scaffold proteins and several kinases in the signal transduction pathways triggered via HER2/HER3, which integrate precise and sequential steps to promote changes in cell morphology to impulse BC cell migration. In addition, we evaluate the effectiveness 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, and promotes actin nucleation in BT-474 BC cells. This signaling is triggered by HER2/HER3 to c-Src, FAK and paxillin. 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 local reorganization of actin fibers.Conclusions:Our findings reveal an original mechanism by which HRG increases BC cell motility, and show that the latter can be abolished by Tz and T-DM1 treatments. These results provide evidence for the molecular mechanisms involved in cell motility and drug resistance. They will be useful to develop new and more specific therapeutic schemes that interfere with the progression and metastasis of HER2+ BC.