Trastuzumab therapy for tamoxifen-stimulated endometrial cancer
Clodia Osipo1, Kathleen Meeke, Hong Liu
1Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
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 17beta-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 alpha (ER alpha) 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 tamoxifen-induced 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 phospho-insulin 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 ER alpha-regulated 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.
Insights
Trastuzumab effectively inhibits both estrogen (E2) and tamoxifen-stimulated endometrial cancer growth by targeting HER-2/neu. This novel therapy shows greater efficacy in tamoxifen-stimulated tumors due to diminished insulin-like growth factor (IGF-I) signaling.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Endometrial cancer (EC) growth can be stimulated by 17beta-estradiol (E2) and tamoxifen, a selective estrogen receptor modulator.
- The role of HER-2/neu in tamoxifen-stimulated EC and its therapeutic targeting remain areas of active investigation.
Purpose of the Study:
- To develop a novel in vivo model of tamoxifen-stimulated endometrial cancer.
- To investigate the role of HER-2/neu in E2- and tamoxifen-stimulated EC using trastuzumab.
- To elucidate the downstream signaling pathways affected by trastuzumab in EC models.
Main Methods:
- Development of tamoxifen-stimulated endometrial cancer xenografts (ECC-1TAM) in vivo.
- Treatment of tumors with 17beta-estradiol (E2), tamoxifen, or raloxifene, and assessment of growth inhibition by trastuzumab.
- Analysis of estrogen receptor alpha (ER alpha) target gene expression (pS2, c-myc) via mRNA.
- Assessment of HER-2/neu, phospho-ERK-1/2, and phospho-Akt protein levels.
- Evaluation of insulin-like growth factor (IGF-I) signaling pathway components (IGF-I, IGF-IR mRNAs, phospho-IRS-1).
Main Results:
- Trastuzumab inhibited E2-stimulated ECC-1E2 tumors by 50% and tamoxifen-stimulated ECC-1TAM tumors by 100%.
- Trastuzumab significantly blocked E2-induced pS2 mRNA and tamoxifen-induced c-myc mRNA expression.
- Trastuzumab decreased phosphorylated and total HER-2/neu protein, and specifically phospho-ERK-1/2 in tamoxifen-treated tumors.
- Diminished IGF-I signaling was observed in ECC-1TAM compared to ECC-1E2 tumors, correlating with enhanced trastuzumab efficacy.
Conclusions:
- Trastuzumab is a potent therapeutic agent for both E2- and tamoxifen-stimulated endometrial cancer.
- Estrogenic activities of E2 and tamoxifen are partly mediated by HER-2/neu.
- Reduced IGF-I signaling enhances trastuzumab's efficacy by enabling complete blockade of downstream phospho-ERK-1/2 signaling in tamoxifen-stimulated EC.
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