Trastuzumab and Pertuzumab Produce Changes in Morphology and Estrogen Receptor Signaling in Ovarian Cancer Xenografts Revealing New Treatment Strategies
- 1 July 2011
- journal article
- Published by American Association for Cancer Research (AACR) in Clinical Cancer Research
- Vol. 17 (13), 4451-4461
- https://doi.org/10.1158/1078-0432.ccr-10-2461
Abstract
Purpose: The aim of this study was to investigate the antitumor effects of HER2-directed combination therapy in ovarian cancer xenograft models to evaluate their potential. The combinations of trastuzumab and pertuzumab, and trastuzumab and aromatase inhibitor therapy were investigated. Experimental Design: The effects of trastuzumab, pertuzumab, and letrozole on growth response, apoptosis, morphology, and gene and protein expression were evaluated in the SKOV3 ovarian cancer cell line xenograft and a panel of five human ovarian xenografts derived directly from clinical specimens. Results: The combination of HER2-directed antibodies showed enhanced antitumor activity compared with single antibody therapy in the SKOV3 xenograft model. Apoptosis, morphology, and estrogen-regulated gene expression were modulated by these antibodies in both spatial and temporal manners. A panel of ovarian cancer xenografts showed differential growth responses to the combination of trastuzumab and pertuzumab. High HER2 expression and increasing HER3 protein expression on treatment were associated with growth response. In trastuzumab-treated SKOV3 tumors, there was a change in tumor morphology, with a reduction in frequency of estrogen receptor alpha (ERα)-negative clear cell areas. Trastuzumab, but not pertuzumab, increased expression of ERα in SKOV3 xenografts when analyzed by quantitative immunofluorescence. ERα and downstream signaling targets were modulated by trastuzumab alone and in combination. Trastuzumab enhanced the responsiveness of SKOV3 xenografts to letrozole when given in combination. Conclusions: These data suggest that trastuzumab in combination with pertuzumab could be an effective approach in high HER2-expressing ovarian cancers and could also enhance sensitivity to endocrine therapy in ERα-positive ovarian cancer. Clin Cancer Res; 17(13); 4451–61. ©2011 AACR.Keywords
Other Versions
This publication has 43 references indexed in Scilit:
- Systems pathology—taking molecular pathology into a new dimensionNature Reviews Clinical Oncology, 2009
- Ligand-Independent HER2/HER3/PI3K Complex Is Disrupted by Trastuzumab and Is Effectively Inhibited by the PI3K Inhibitor GDC-0941Cancer Cell, 2009
- Trastuzumab Reverses Letrozole Resistance and Amplifies the Sensitivity of Breast Cancer Cells to EstrogenCancer Research, 2009
- Molecular response to aromatase inhibitor treatment in primary breast cancerBreast Cancer Research, 2007
- Ovarian clear cell adenocarcinoma: a continuing enigmaJournal of Clinical Pathology, 2006
- Insights into ErbB signaling from the structure of the ErbB2-pertuzumab complexCancer Cell, 2004
- Structure of the extracellular region of HER2 alone and in complex with the Herceptin FabNature, 2003
- Randomized Intergroup Trial of Cisplatin-Paclitaxel Versus Cisplatin-Cyclophosphamide in Women With Advanced Epithelial Ovarian Cancer: Three-Year ResultsJNCI Journal of the National Cancer Institute, 2000
- Tissue microarrays for high-throughput molecular profiling of tumor specimensNature Medicine, 1998
- Cyclophosphamide and Cisplatin Compared with Paclitaxel and Cisplatin in Patients with Stage III and Stage IV Ovarian CancerNew England Journal of Medicine, 1996