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Amplification of PVT1 Contributes to the Pathophysiology of Ovarian and Breast Cancer

Authors' Affiliations: ¹ Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California; ² Department of Laboratory Medicine, ³ Cancer Research Institute, and ⁴ Department of Neurosurgery Research, University of California at San Francisco, San Francisco, California; ⁵ Trubion Pharmaceuticals, Seattle, Washington; ⁶ Department of Obstetrics and Gynecology, Jikei University School of Medicine, Tokyo, Japan; ⁷ Genentech, Inc., South San Francisco, California; and ⁸ Centre for Translational and Applied Genomics; ⁹ Cheryl Brown Ovarian Cancer Outcomes Unit of the British Columbia Cancer Agency; ¹⁰ Department of Pathology, University of British Columbia, Vancouver General Hospital and British Columbia Cancer Agency, Vancouver, British Columbia, Canada; and ¹¹ Department of Molecular Therapeutics, M.D. Anderson Cancer Center, Houston, Texas

Requests for reprints: Joe W. Gray, Life Sciences Division, Lawrence Berkeley National Laboratory, One Cyclotron Road, MS977/225A, Berkeley, CA 94720. Phone: 510-495-2438; Fax: 510-495-2535; E-mail: jwgray{at}lbl.gov.

Purpose: This study was designed to elucidate the role of amplification at 8q24 in the pathophysiology of ovarian and breast cancer because increased copy number at this locus is one of the most frequent genomic abnormalities in these cancers.

Experimental Design: To accomplish this, we assessed the association of amplification at 8q24 with outcome in ovarian cancers using fluorescence in situ hybridization to tissue microarrays and measured responses of ovarian and breast cancer cell lines to specific small interfering RNAs against the oncogene MYC and a putative noncoding RNA, PVT1, both of which map to 8q24.

Results: Amplification of 8q24 was associated with significantly reduced survival duration. In addition, small interfering RNA–mediated reduction in either PVT1 or MYC expression inhibited proliferation in breast and ovarian cancer cell lines in which they were both amplified and overexpressed but not in lines in which they were not amplified/overexpressed. Inhibition of PVT1 expression also induced a strong apoptotic response in cell lines in which it was overexpressed but not in lines in which it was not amplified/overexpressed. Inhibition of MYC, on the other hand, did not induce an apoptotic response in cell lines in which MYC was amplified and overexpressed.

Conclusions: These results suggest that MYC and PVT1 contribute independently to ovarian and breast pathogenesis when overexpressed because of genomic abnormalities. They also suggest that PVT1-mediated inhibition of apoptosis may explain why amplification of 8q24 is associated with reduced survival duration in patients treated with agents that act through apoptotic mechanisms.

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