Abstract 1664: Maternal embryonic leucine aipper kinase (MELK) is a critical regulator of proliferation and is independently prognostic in estrogen receptor-negative breast cancer

Abstract

Abstract Background: Molecularly targeted therapies such as tamoxifen, aromatase inhibitors, and trastuzumab are useful for the treatment of breast cancer. However, these targeted therapies do not treat all breast cancers, especially estrogen receptor alpha (ER)-negative, progesterone receptor (PR)-negative, HER2-negative (“triple-negative”) breast cancer. Our lab previously used gene expression profiling of human breast cancers to identify kinases overexpressed in ER-negative breast cancers. One of the kinases highly expressed in a poor prognosis group of triple negative breast cancers is maternal embryonic leucine-zipper kinase (MELK). The purpose of this study was to demonstrate that MELK expression is upregulated in ER-negative breast cancers, and to test the hypothesis that MELK is a critical regulator of ER-negative breast cancer cell growth. Methods: RNA from breast cancer cell lines and 60 human breast tumors was isolated for Q-PCR analysis of MELK. To determine if MELK regulates cell proliferation, ER-positive and ER-negative breast cancer cell lines were transfected with siRNA targeting MELK. Cells were replated 36 hours after transfection in 96-well plates at a density of 2,000/well. Cell number was measured by the MTS assay every day for 6 days. To determine if MELK levels are independently prognostic, we performed uni- and multivariate Cox regression analysis, including all available biological characteristics of the tumor in the model. Results: MELK mRNA levels were significantly higher (p<0.02) in ER-negative breast cancers (20.2 ± 7 fold) compared to ER-positive breast cancers (5.0 ± 2 fold). In 6 of 7 ER-negative cell lines, MELK knockdown suppressed growth (≥50% growth inhibition) compared to cells transfected with control siRNA. MELK knockdown had little to no effect on growth of the 3 ER-positive cell lines tested. Importantly, in a multivariate Cox proportional hazards model, high MELK expression was shown to be independently associated with a poor prognosis, [HR=1.19 95% CI: (1.05, 1.36) p=0.007]. Current studies are focused on understanding how MELK regulates ER-negative cell growth, using ER-negative cell lines stably expressing an inducible dominant negative MELK protein. Conclusions: MELK is highly expressed in ER-negative breast cancer, essential for ER-negative breast cancer cell growth, and is independently prognostic. These findings suggest that MELK is a promising target for the treatment of ER-negative breast cancer. Supported by a Susan G. Komen for the Cure Promise Grant. (KG081694). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1664. doi:10.1158/1538-7445.AM2011-1664