Breast cancer is a heterogeneous disease, classified into different subtypes with varying clinical prognoses and treatment strategies. Although ERBB3/HER3 and its partner ERBB2/HER2 are expressed at low levels in basal-like/triple-negative breast cancer, stratified analysis of basal-like breast cancer patients based on ERBB3 mRNA expression levels revealed that higher ERBB3 expression levels were associated with shorter recurrence-free survival. In vitro analyses showed that activation of the NRG1/ERBB3/ERBB2 axis significantly induced anchorage-independent growth in a basal-like/triple-negative breast cancer cell model without significantly affecting cell proliferation, differentiation, and migration in adhesion. Overall, these data suggest that ERBB2/ERBB3 plays an oncogenic role in basal-like/triple-negative breast cancer, suggesting that neutralizing ERBB2/ERBB3 could be a potential treatment strategy for these breast cancer subtypes, where current treatment options are very limited.
Approximately 25% of HER2-negative triple-negative breast cancers in primary tumors transform into HER2-low-expressing tumors in recurrent tumors, maintaining the same cancer phenotype. Here, the study suggests that loss of cell adhesion may promote ERBB2 upregulation. Researchers also used stably ERBB2-overexpressing MCF10A cells (MCF10A-HER2) to evaluate the role of the NRG1β/ERBB3/ERBB2 axis in basal-like cells with increased expression of ERBB2. Compared to untreated control cells, administration of NRG1β to ERBB2-overexpressing MCF10A cells induced an increase in the number and size of spheroid, which was significantly inhibited by pertuzumab, but not by trastuzumab in combination (Figures 1a-c). Overall, these data suggest that pertuzumab effectively inhibits NRG1β-induced basal-like breast cell growth even with ERBB2 upregulation.
Figure 1. Administration of NRG1β promotes growth in non-adherent conditions in basal-like/triple-negative breast cells engineered with HER2 overexpression. (Miano C, et al., 2022)