Abstract 2853: Discovery of phosphatases that regulate growth and tumorigenicity of ER-negative breast cancers

Abstract

Abstract Background: As the leading cause of cancer-related death in women, there is an urgent need to identify therapeutic means for breast cancer in women. 60-70% of breast cancers express the estrogen receptor (ER) and respond to therapies targeting this receptor. The remaining 30-40% of breast cancers that do not express this receptor are cannot be treated with these therapies. To identify novel targets for treatment, we are investigating growth-regulatory pathways in ER-negative breast cancers. The goal is to identify phosphatases that are critical for the growth and tumorigenicity of ER-negative breast cancer. Methods: To identify signaling pathways important in ER-negative breast cancer, we used Affymetrix microarray data obtained from profiling 221 ER-negative and 56 ER-positive breast cancers from the Baylor College of Medicine Tumor Bank. We then performed supervised cluster analysis to identify phosphatases that were differentially expressed in ER-negative and ER-positive breast cancers. This analysis identified 20 phosphatases upregulated (>1.5-fold; FDR=0.05), and 29 phosphatases down-regulated (< 0.66-fold, FDR=0.05) in ER-negative breast cancers as compared to ER-positive breast cancers. Specific siRNA were used to knock-down each of the 20 highly expressed phosphatases in 4 ER-negative, 4 ER-positive breast cancer cell lines, HMECs immortalized with TERT, and HMECs. Cell growth was measured by cell count, and anchorage-independent growth was tested with the soft agar assay. Colonies were counted after 14 days with the Gelcount software. Results: Of the 20 overexpressed phosphatases, 9 showed significant growth reduction after treatment with siRNA in at least 2 of the 4 ER-negative breast cancer cell lines. These 9 phosphatases are now being tested in anchorage-independent growth assays. Based on our results, 3 phosphatases (ACP1, PTP4A3, and CDC25B) have been selected for further study. These are now being tested for their transforming capability in in vitro and in vivo transformation and tumorigenicity assays. Conclusion: We identified a set of phosphatases highly over-expressed in ER-negative breast cancer, and showed that a sub-set of these phosphatases are critical for anchorage-dependent and -independent breast cancer cell growth. These studies have identified critical growth-regulatory phosphatases in ER-negative breast tumors that may be novel targets for the treatment of ER-negative breast cancer. Supported by Komen Promise grant KG081694 (PHB) & Komen SAB grant SAB08-00006 (PHB). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2853. doi:1538-7445.AM2012-2853