Breast Cancer Awareness: Maternal Embryonic Leucine Zipper Kinase Is Upregulated and Required in Mammary Tumor-Initiating Cells In vivo

Maternal Embryonic Leucine Zipper Kinase Is Upregulated and Required in Mammary Tumor-Initiating Cells In vivo — Cancer Res

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Maternal Embryonic Leucine Zipper Kinase Is Upregulated and Required in Mammary Tumor-Initiating Cells In vivo Lionel W. Hebbard 1, Jochen Maurer 1, Amber Miller 1, Jacqueline Lesperance 1, John Hassell 2, Robert G. Oshima 1, and Alexey V. Terskikh 1

Authors' Affiliations:1Tumor Development Program, Cancer Research Center, Sanford-Burnham Medical Research Institute, La Jolla, California and 2Center for Functional Genomics, Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada Corresponding Authors:
Robert G. Oshima or Alexey Terskikh, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037. Phone: 858-795-5299; Fax: 858-795-5298; E-mail: rgoshima{at}burnham.org or terskikh{at}burnham.org. Current address for L. Hebbard: Westmead Millennium Institute, P.O. Box 412, Westmead NSW 2145, Australia.

Note: R.G. Oshima and A. Terskikh contributed equally to this work.

Abstract Maternal embryonic leucine zipper kinase (MELK) is expressed in several developing tissues, in the adult germ line, and in adult neural progenitors. MELK expression is elevated in aggressive undifferentiated tumors, correlating with poor patient outcome in human breast cancer. To investigate the role of MELK in mammary tumorigenesis in vivo, we used a MELK-green fluorescent protein (GFP) reporter mouse, which allows prospective isolation of MELK-expressing cells based on GFP fluorescence. We found that in the normal mammary gland, cells expressing high levels of MELK were enriched in proliferating cells that express markers of mammary progenitors. The isolation of cells with high levels of MELK in mammary tumors from MMTV-Wnt1/MELK-GFP bitransgenic mice resulted in a significant enrichment of tumorsphere formation in culture and tumor initiation after transplantation into mammary fat pads of syngeneic mice. Furthermore, using lentiviral delivery of MELK-specific shRNA and limiting dilution cell transplantations, we showed that MELK function is required for mammary tumorigenesis in vivo. Our findings identify MELK as a potential target in breast tumor-initiating cells. Cancer Res; 70(21); 8863–73. ©2010 AACR.