SHORT COMMUNICATION aPKCf cortical loading is associated with Lgl cytoplasmic release and tumor growth in Drosophila and human epithelia D Grifoni 1,2,6 , F Garoia 1,6 , P Bellosta 3 , F Parisi 1 , D De Biase 4 , G Collina 4 , D Strand 5 , S Cavicchi 1 and A Pession 2,4 1 Dipartimento di Biologia Evoluzionistica Sperimentale, Alma Mater Studiorum, Bologna, Italy; 2 Dipartimento di Patologia Sperimentale, Alma Mater Studiorum, Bologna, Italy; 3 Biology Department, City College of New York – CUNY, New York, NY, USA; 4 Alma Mater Studiorum, Sezione di Anatomia Patologica, Ospedale Bellaria, Bologna, Italy and 5 First Department of Internal Medicine, Johannes Gutenberg University, Mainz, Germany Atypical protein kinase C (aPKC) and Lethal giant larvae (Lgl) regulate apical–basal polarity in Drosophila and mammalian epithelia. At the apical domain, aPKC phosphorylates and displaces Lgl that, in turn, maintains aPKC inactive at the basolateral region. The mutual exclusion of these two proteins seems to be crucial for the correct epithelial structure and function. Here we show that a cortical aPKC loading induces Lgl cytoplasmic release and massive overgrowth in Drosophila imaginal epithelia, whereas a cytoplasmic expression does not alter proliferation and epithelial overall structure. As two aPKC isoforms (i and f) exist in humans and we previously showed that Drosophila Lgl is the functional homologue of the Human giant larvae-1 (Hugl-1) protein, we argued if the same mechanism of mutual exclusion could be impaired in human epithelial disorders and investigated aPKCi, aPKCf and Hugl-1 localization in cancers deriving from ovarian surface epithelium. Both in mucinous and serous histotypes, aPKCf showed an apical-to-cortical redistribution and Hugl-1 showed a membrane-to-cytoplasm release, perfectly recapitulating the Drosophila model. Although several recent works support a causative role for aPKCi overexpression in human carcinomas, our results suggest a key role for aPKCf in apical–basal polarity loosening, a mechanism that seems to be driven by changes in protein localization rather than in protein abundance. Oncogene (2007) 26, 5960–5965; doi:10.1038/sj.onc.1210389; published online 19 March 2007 Keywords: Lethal giant larvae; Hugl-1; aPKCz; cell polarity; ovarian epithelial cancers; Drosophila A correct apical–basal cell polarity is the main feature of a healthy epithelial tissue (Nelson, 2003). From invertebrates to mammals, cells composing the epithelial sheets possess complex junctional structures that define an apical and a basolateral domain, favor cell–cell communication and cytoskeleton architecture, restrict motility and maintain tissue integrity making the cell layer work as a functional unit (Pilot and Lecuit, 2005; Christiansen and Rajasekaran, 2006; Shin et al., 2006). Loosening of these complexes is often associated to epithelial cancer progression, especially during the epithelial-to-mesenchymal transition (reviewed in Thiery, 2002), also if tumors exist in which cells exhibit diverse differentiated phenotypes as it is emer- ging from cancer stem cells theory (Polyak and Hahn, 2006; Filip et al., 2006). Ovarian carcinoma is a highly lethal form of cancer (Scott and McCluggage, 2006); the lack of appropriate animal models has strongly delayed either morphological or genetic characterization (Vanderhyden et al., 2003) and the mesothelial origin of the ovarian surface epithelium (OSE) has long kept researchers away from considering this tissue as a potential source of ovarian carcinomas (Auersperg et al., 2001). Only in the late 1980s methods to culture OSE have become available (Siemens and Auersperg, 1988) and genetic approaches led to conclusive evidence that mucinous and serous histotypes derive from OSE cells, whereas endometrioid and clear-cells subtypes are rather believed to arise from ectopic endometrium (Auersperg et al., 2001; Katabuchi and Okamura, 2003; Bell, 2005). OSE is a monolayer of a flat-to- cuboidal epithelium coating human ovaries and cortical inclusion cysts in which cell–cell adhesiveness is not so strong (Sundfeldt, 2003): the cyclic rupture and pro- liferative repair at the sites of ovulation are probably a reason for this junctional plasticity (Katabuchi and Okamura, 2003; Okamura et al., 2006). Curiously, opposite to the majority of carcinomas, a columnar, more cohesive morphology is for OSE the first step towards malignancy (Ong et al., 2000; Sarrı´o et al., 2006). In the most advanced stages, however, both mucinous and serous carcinomas are composed of dedifferentiated, round-shaped cells that grow in 3D and exfoliate giving rise to local metastases vehiculated by peritoneal fluids (Auersperg et al., 2001; Naora and Montell, 2005). A genetic link between cell shape and Received 20 December 2006; revised 6 February 2007; accepted 8 February 2007; published online 19 March 2007 Correspondence: D Grifoni, Alma Mater Studiorum, Dipartimento di Biologia Evoluzionistica Sperimentale, Via Selmi 3, 40126 Bologna, Italy. E-mail: daniela.grifoni@unibo.it 6 These two authors contributed equally to this work. Oncogene (2007) 26, 5960–5965 & 2007 Nature Publishing Group All rights reserved 0950-9232/07 $30.00 www.nature.com/onc