Trastuzumab Therapy for Tamoxifen-Stimulated Endometrial Cancer

Abstract

A novel in vivo model of tamoxifen-stimulated endometrial cancer was developed and the role of HER-2/neu investigated by using trastuzumab. Tamoxifen-stimulated tumors (ECC-1TAM) were growth stimulated by 17B-estradiol (E2), tamoxifen, or raloxifene. Trastuzumab inhibited growth of E2-stimulated ECC-1E2 tumors by 50% and tamoxifen-stimulated ECC-1TAM tumors by 100%. ECC-1 tumors expressed functional estrogen receptor A (ERA) as measured by induction of pS2 and c-myc mRNAs. E2 induced pS2 and c-myc mRNAs up to 40-fold in ECC-1E2 and ECC-1TAM. Tamoxifen induced pS2 and c-myc mRNAs up to 5-fold in ECC-1E2 tumors and up to 10-fold in ECC-TAM tumors. Trastuzumab blocked E2-induced pS2 mRNA (P < 0.01) in ECC-1E2 by 50% and tamoxifeninduced c-myc mRNA (P < 0.1) in ECC-1TAM tumors by 70%. Trastuzumab decreased phosphorylated and total HER-2/neu protein in ECC-1E2 and ECC-1TAM tumors. However, only phospho-ERK-1/2 and not phospho-Akt protein was decreased by trastuzumab in tamoxifen-treated ECC-1TAM tumors. The insulin-like growth factor (IGF-I) signaling pathway also activates extracellular signal-related kinase (ERK)-1/2 and could block the efficacy of trastuzumab in ECC-1E2 tumors. The results showed that IGF-I, IGF-IR mRNAs, and phosphoinsulin receptor substrate-1 (IRS-1) protein were decreased in ECC-1TAM compared with ECC-1E2 tumors. The results show that trastuzumab is an effective therapy for both E2-stimulated and tamoxifen-stimulated endometrial cancer. The data suggest estrogenic activities of E2 and tamoxifen at ERAregulated pS2 and c-myc genes are in part mediated by HER-2/ neu. However, trastuzumab is a better growth inhibitor of ECC-1TAM tumors where there is diminished IGF-I signaling allowing for complete blockade of the downstream phospho-ERK-1/2 signal. (Cancer Res 2005; 65(18): 8504-13)

Gallic acid suppresses the migration and invasion of PC-3 human prostate cancer cells via inhibition of matrix metalloproteinase-2 and -9 signaling pathways

“…It was reported that PI3K activation stimulated the downstream target AKT which associated with cell invasion (38,39). Other investigators have pointed out that PI3K activation stimulated the downstream target AKT, and AKT plays various and important roles in cell invasion (38)(39)(40) and the activation of ERK and AKT are involved in the development of endometrial cancer (41,42). Herein, our findings showed that GA inhibited the protein levels of PI3K, AKT, PKC, NF-κB, MMP-2 and MMP-9 in PC-3 cells in vitro.…”

A novel variant of ER-alpha, ER-alpha36 mediates testosterone-stimulated ERK and Akt activation in endometrial cancer Hec1A cells

“…It is possible that increased rate by which androgen is converted to estrogen via aromatization, which then stimulates both the MAPK/ERK and the PI3K/Akt signaling pathways through ER-α36. The activation of ERK and Akt is involved the development of endometrial cancer [ 15 , 41 ].…”

Targeting both Notch and ErbB-2 signalling pathways is required for prevention of ErbB-2-positive breast tumour recurrence

“…Each mouse was tagged on one ear to identify the specific mouse and tumour. Once tumours grew to a mean cross-sectional area (CRA) of 0.20–0.30 cm 2 , mice were killed; tumours were extracted and re-transplanted into a set of 56 mice as previously described (Osipo et al , 2005b). Tumours were allowed to grow to a mean CRA of 0.20–0.30 cm 2 and mice were randomised to four treatment groups with 14 mice per group: vehicle control (sterile PBS and 2% carboxymethylcellulose), trastuzumab (10 mg kg −1 in a total volume of 100  μ l sterile PBS, i.p.…”