LKB1 as a Tumor Suppressor in Uterine Cancer: Mouse Models and Translational Studies
The LKB1 tumor suppressor was identified in 1998 as the gene mutated in the Peutz–Jeghers Syndrome (PJS), a hereditary cancer predisposition characterized by gastrointestinal polyposis and a high incidence of cancers, particularly carcinomas, at a variety
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LKB1 as a Tumor Suppressor in Uterine Cancer: Mouse Models and Translational Studies Christopher G. Peña and Diego H. Castrillón
Abstract The LKB1 tumor suppressor was identified in 1998 as the gene mutated in the Peutz–Jeghers Syndrome (PJS), a hereditary cancer predisposition characterized by gastrointestinal polyposis and a high incidence of cancers, particularly carcinomas, at a variety of anatomic sites including the gastrointestinal tract, lung, and female reproductive tract. Women with PJS have a high incidence of carcinomas of the uterine corpus (endometrium) and cervix. The LKB1 gene is also somatically mutated in human cancers arising at these sites. Work in mouse models has highlighted the potency of LKB1 as an endometrial tumor suppressor and its distinctive roles in driving invasive and metastatic growth. These in vivo models represent tractable experimental systems for the discovery of underlying biological principles and molecular processes regulated by LKB1 in the context of tumorigenesis and also serve as useful preclinical model systems for experimental therapeutics. Here we review LKB1’s known roles in mTOR signaling, metabolism, and cell polarity, with an emphasis on human pathology and mouse models relevant to uterine carcinogenesis, including cancers of the uterine corpus and cervix. Keywords LKB1 • STK11 • Endometrial cancer • Uterine cancer • Genetically engineered mouse models • MTOR • AMPK • Therapeutics
Introduction In humans, the LKB1 (Liver Kinase B1) gene, a.k.a. STK11 (Serine Threonine Kinase 11), is located on chromosome 19p13.3 and encodes a serine/threonine kinase with important roles in human disease, particularly cancer [1]. The LKB1 C.G. Peña, Ph.D. (*) Department of Cell Systems and Anatomy, UT Health Science Center at San Antonio, MED 552C7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA e-mail: [email protected] D.H. Castrillón, M.D., Ph.D. Department of Pathology, UT Southwestern Medical Center, Dallas, TX 75390-9072, USA e-mail: [email protected] © Springer International Publishing AG 2017 L. Hedrick Ellenson (ed.), Molecular Genetics of Endometrial Carcinoma, Advances in Experimental Medicine and Biology 943, DOI 10.1007/978-3-319-43139-0_7
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C.G. Peña and D.H. Castrillón
gene contains 9 coding exons [2], resulting in a 433 amino acid intracellular kinase (48 kDa) [3] that regulates diverse aspects of cellular physiology including metabolism, growth and proliferation, and cellular polarity, among other functions. Ubiquitous expression of LKB1 in adult tissues [4] and its conservation from fruit flies to mammals [5], together with many functional investigations into its biological roles in these diverse organisms, have established the universality of many of these essential cellular functions. In mammals, germline (hereditary) or somatic (acquired) mutations in LKB1 provoke a variety of tumors. LKB1 was originally identified as the gene responsible for the Peutz–Jeghers Syndrome (PJS), an autosomal dominant condition cha
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