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Zhi Hu, Richard Neve, Yinghui Guan, and Joe Gray

Identification of new therapeutic targets of breast cancer using siRNA technology
AACR Meeting Abstracts 2007: 4956.

Abstract 1 of 1

Target Identification and Validation: Large Scale Approaches: Oral Presentations - Proffered Abstracts

Abstract #4956

Identification of new therapeutic targets of breast cancer using siRNA technology

Lawrence Berkeley National Laboratory, Berkeley, CA

Background and Purpose From a comprehensive study of gene expression and copy number in primary breast cancers and breast cancer cell lines^1,2, we have identified regions of high level amplification on chromosomes 1q21, 8p11, 11q13, 17q12 and 20q13 that are associated with reduced survival duration. The annexin family member, ANXA9, and the metalloproteinase-like, disintegrin-link and cysteine-rich protein, ADAM9, map to the regions of amplification at 1q21 and 8p11, respectively. We have applied siRNA knockdown to explore the hypothesis that amplification and over-expression of these genes plays a role in breast cancer pathophysiology and that these genes may be important therapeutic targets. Experimental procedures We transiently transfected 83nM of siRNA for ANXA9 and ADAM9 into T47D, BT549, SUM52PE, 600MPE and MCF10A breast cancer cell lines. Non-specific siRNA served as a negative control. Cell viability/proliferation was evaluated by Cell Titer-Glo luminescent cell viability assay (CTG, Promega), cell apoptosis was assayed using YoPro-1 and Hoechst staining and cell cycle inhibition was assessed by measuring BrdU incorporation. All cellular measurements were made in adhered cells using the Cellomics high content scanning instrument. All assays were run at 3, 4, 5 and 6 days post transfection. Results Approximately 70-80% knockdown of ANXA9 was achieved in BT549 and T47D cells transfected with siRNA-ANXA9 for 48hr, 72hr and 96hr. Silencing of ANXA9 and ADAM9 significantly reduced the proliferation of breast cancer cells and inhibited the BrdU incorporation after treatment with siRNA compared to controls. Knockdown of ANXA9 and ADAM9 in breast cancer cells also induced significant levels of apoptosis. Furthermore, we found that cells had very good response when the concentration of siRNA-ANXA9 and siRNA-ADAM9 were higher than 30nM. Conclusion The current results suggested that silencing expression of ANXA9 and ADAM9 is a novel approach for inhibition of breast cancer cell growth. ANXA9 and ADAM9 may serve as new candidate therapeutic targets for treatment of breast cancer with poor outcome.

1. Chin, K. et al. Genomic and transcriptional aberrations linked to breast cancer pathophysiologies. Cancer Cell In Press (2006)

2. Neve, R.M. et al. A collection of breast cancer cell lines for study of functionally distinct cancer subtypes. Cancer Cell In Press (2006)