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Vol. 20, Issue 11, 2785-2795, June 1, 2009

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LKB1 Catalytic Activity Contributes to Estrogen Receptor Signaling

Faculty of Medicine, Department of Biochemistry and Molecular Biology, Dalhousie University, Halifax, Nova Scotia, Canada B3H1X5

Submitted November 21, 2008; Revised March 12, 2009; Accepted April 1, 2009
Monitoring Editor: William P. Tansey

The tumor suppressor serine-threonine kinase LKB1 is mutated in Peutz-Jeghers syndrome (PJS) and in epithelial cancers, including hormone-sensitive organs such as breast, ovaries, testes, and prostate. Clinical studies in breast cancer patients show low LKB1 expression is related to poor prognosis, whereas in PJS, the risk of breast cancer is similar to the risk from germline mutations in breast cancer (BRCA) 1/BRCA2. In this study, we investigate the role of LKB1 in estrogen receptor (ER) signaling. We demonstrate for the first time that LKB1 binds to ER in the cell nucleus in which it is recruited to the promoter of ER-responsive genes. Furthermore, LKB1 catalytic activity enhances ER transactivation compared with LKB1 catalytically deficient mutants. The significance of our discovery is that we demonstrate for the first time a novel functional link between LKB1 and ER. Our discovery places LKB1 in a coactivator role for ER signaling, broadening the scientific scope of this tumor suppressor kinase and laying the groundwork for the use of LKB1 as a target for the development of new therapies against breast cancer.

Address correspondence to: Paola A. Marignani (pmarigna{at}dal.ca).

Abbreviations used: 4-OHT, 4-hydroxy tamoxifen; E2, 17β-estradiol; ER, estrogen receptor ; ERE, estrogen response element; PJS, Peutz-Jeghers syndrome; TnT, transcribed and translated.