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Open Access Research article

Integrated genomics of ovarian xenograft tumor progression and chemotherapy response

Ashley Stuckey1, Andrew Fischer2, Daniel H Miller2, Sara Hillenmeyer2, Kyu K Kim1, Anna Ritz3, Rakesh K Singh1, Benjamin J Raphael3, Laurent Brard4 and Alexander S Brodsky2*

Author Affiliations

1 Molecular Therapeutics Laboratory, Program in Women's Oncology, Department of Obstetrics and Gynecology, Women and Infants7 Hospital, Alpert Medical School of Brown University, Providence, RI 02905, USA

2 Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, RI 02903, USA

3 Department of Computer Science & Center for Computational Molecular Biology, Brown University, Providence, RI 02912, USA

4 Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Southern Illinois University School of Medicine, Springfield, IL 62794-9640, USA

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BMC Cancer 2011, 11:308  doi:10.1186/1471-2407-11-308

Published: 22 July 2011

Abstract

Background

Ovarian cancer is the most deadly gynecological cancer with a very poor prognosis. Xenograft mouse models have proven to be one very useful tool in testing candidate therapeutic agents and gene function in vivo. In this study we identify genes and gene networks important for the efficacy of a pre-clinical anti-tumor therapeutic, MT19c.

Methods

In order to understand how ovarian xenograft tumors may be growing and responding to anti-tumor therapeutics, we used genome-wide mRNA expression and DNA copy number measurements to identify key genes and pathways that may be critical for SKOV-3 xenograft tumor progression. We compared SKOV-3 xenografts treated with the ergocalciferol derived, MT19c, to untreated tumors collected at multiple time points. Cell viability assays were used to test the function of the PPARγ agonist, Rosiglitazone, on SKOV-3 cell growth.

Results

These data indicate that a number of known survival and growth pathways including Notch signaling and general apoptosis factors are differentially expressed in treated vs. untreated xenografts. As tumors grow, cell cycle and DNA replication genes show increased expression, consistent with faster growth. The steroid nuclear receptor, PPARγ, was significantly up-regulated in MT19c treated xenografts. Surprisingly, stimulation of PPARγ with Rosiglitazone reduced the efficacy of MT19c and cisplatin suggesting that PPARγ is regulating a survival pathway in SKOV-3 cells. To identify which genes may be important for tumor growth and treatment response, we observed that MT19c down-regulates some high copy number genes and stimulates expression of some low copy number genes suggesting that these genes are particularly important for SKOV-3 xenograft growth and survival.

Conclusions

We have characterized the time dependent responses of ovarian xenograft tumors to the vitamin D analog, MT19c. Our results suggest that PPARγ promotes survival for some ovarian tumor cells. We propose that a combination of regulated expression and copy number can identify genes that are likely important for chemotherapy response. Our findings suggest a new approach to identify candidate genes that are critical for anti-tumor therapy.