Lapatinib can activate or supress estrogen receptor (ER) signaling in cell models of endocrine resistant breast cancer.

Abstract

Abstract Abstract #3031 Background
 Growth factor (GF) signaling is frequently upregulated in hormone resistant breast cancer (BC) and provides the rationale for using the dual EGFR/HER2 inhibitor, lapatinib (LAP) in an effort to overcome endocrine resistance. Hormone resistant BC can also vary in its degree of continued ER dependence. We previously demonstrated potent synergy between LAP and TAM in cell models of acquired endocrine resistance to tamoxifen (TAMR cells), and to estrogen deprivation (LTED cells)1. This study aimed to characterize the phenotype of these two models with a focus on the ER pathway, and to determine the biological basis for the observed synergy between LAP and TAM.
 Methods
 LTED cells and TAMR cells were both derived from hormone-sensitive MCF7 parental cells as previously described1. The differential effects of LAP, TAM, estrogen deprivation (ED) or the combination were assessed by proliferation assays, ERE reporter assays, quantitative PCR and western blot analyses.
 Results
 In LTEDs: Increased ER expression and ERE transactivation were seen in LTEDs compared to MCF7 cells, as well as continued sensitivity to the ER downregulator, fulvestrant (FUL), indicating that in LTEDs, ER activity is not only enhanced but is also a significant driver of growth. In LTEDs, LAP alone suppressed ER activity as measured by both ERE transactivation and ER phosphorylation at Ser118; the most effective suppression of ER activity was achieved with a combination of LAP+TAM/ED where the effects were additive.
 In TAMRs: In contrast, TAMRs demonstrated decreased ER activity (low basal ERE transactivation and loss of PgR) and ER independent proliferation (FUL had minimal growth inhibitory effects despite ER downregulation). In TAMRs, neither LAP nor TAM had significant antiproliferative effects on their own: LAP alone decreased pMAPK/pAkt but increased basal ERE transactivation and transcription of the ER-responsive gene pS2. TAM alone inhibited ERE activation but increased HER2 gene and protein expression. Inhibiting both HER2 and ER pathways with LAP+TAM resulted in synergistic growth inhibition.
 Conclusions
 In LTED cells with enhanced ER function attributable in part to GF receptor activation, the synergistic antiproliferative effects from LAP and TAM or ED may be largely due to enhanced inhibition of ER signaling. In contrast in TAMR cells with suppressed ER activity, LAP alone appears to enhance ER signaling, while TAM alone inhibits ER activity but increases HER2 expression. In TAMRs, the combination of TAM+LAP is required to interrupt both ER and GF signaling. These results suggest that the basis for synergy between LAP and endocrine therapy in hormone resistant BC may vary depending on the nature of the cross-talk between the ER and GF pathways.
 1SABCS, 2006 Abs 303. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3031.