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PIK3CA and APC Mutations Are Synergistic in the Development of Intestinal Cancers

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PIK3CA and APC Mutations Are Synergistic in the Development of Intestinal Cancers Oncogene (2014) 33, 2245–2254 & 2014 Macmillan Publishers Limited All rights reserved 0950-9232/14 www.nature.com/onc ORIGINAL ARTICLE PIK3CA and APC mutations are synergistic in the development of intestinal cancers DA Deming1, AA Leystra2, L Nettekoven3, C Sievers4, D Miller3, M Middlebrooks3, L Clipson2, D Albrecht3, J Bacher5, MK Washington6, J Weichert7 and RB Halberg3 Human colorectal cancers are known to possess multiple mutations, though how these mutations interact in tumor development and progression has not been fully investigated. We have previously described the FCPIK3ca* murine colon cancer model, which expresses a constitutively activated phosphoinositide-3 kinase (PI3K) in the intestinal epithelium. The expression of this dominantly active form of PI3K results in hyperplasia and invasive mucinous adenocarcinomas. These cancers form via a non-canonical mechanism of tumor initiation that is mediated through activation of PI3K and not through aberrations in WNT signaling. Since the Adenomatous Polyposis Coli (APC) gene is mutated in the majority of human colon cancers and often occurs simultaneously with PIK3CA mutations, we sought to better understand the interaction between APC and PIK3CA mutations in the mammalian intestine. In this study, we have generated mice in which the expression of a constitutively active PI3K and the loss of APC occur simultaneously in the distal small intestine and colon. Here, we demonstrate that expression of a dominant active PI3K synergizes with loss of APC activity resulting in a dramatic change in tumor multiplicity, size, morphology and invasiveness. Activation of the PI3K pathway is not able to directly activate WNT signaling through the nuclear localization of CTNNB1 (b-catenin) in the absence of aberrant WNT signaling. Alterations at the transcriptional level, including increased CCND1, may be the etiology of synergy between these activated pathways. Oncogene (2014) 33, 2245–2254; doi:10.1038/onc.2013.167; published online 27 May 2013 Keywords: colon cancer; APC; PI3K; PIK3CA; mouse models INTRODUCTION cancer types, including 20–30% of colorectal cancers.8 Mutations Colorectal adenocarcinoma continues to be a major etiology of of the PIK3CA gene encode for a dominant active form of the morbidity and mortality despite significant advances in the p110a catalytic subunit of PI3K and occur in three hotspots: E454K, understanding of tumor biology and treatment options.1 The E456K and H1047R.9 PIK3CA mutations have been investigated in profile of mutations has now been characterized in multiple numerous cancer cell lines; however, until recently the effect of a human cancers; however, the role of these mutations in dominant active PI3K in the mammalian intestine had not been tumorigenesis, progression and response to therapy has largely investigated. Our laboratory has developed a murine model, yet to be defined.2 FCPIK3ca*, that expresses a dominant active form of PI3K Adenomatous Polyposis Coli (APC) mutations have been well (p110*) in the distal small bowel and colon.10 This model characterized as important mediators of colorectal tumorigenesis.3 develops sessile large moderately differentiated invasive mucinous Germline mutations were discovered in patients with familial adenocarcinomas in the proximal colon through a non-canonical adenomatous polyposis, but somatic mutations are also present in mechanism and without a polypoid luminal component. 80–90% of sporadic colorectal polyps and cancers.4 These APC and PIK3CA mutations are commonly identified together in mutations lead to truncation of the APC protein resulting in the human colorectal cancers, yet the interaction between these loss of function of this tumor suppressor. Loss of APC function mutations remains to be investigated in the mammalian intes- results in dysregulation of CTNNB1 (b-catenin), leading to tine.11 The potential for cross-talk between these signaling increased WNT pathway signaling through MYC and CCND1 cascades has been an area of interest. These pathways converge (cyclin D1), among others.5 The ApcMin/ þ (Min) mouse carries a on glycogen synthase kinase 3 (GSK3) and potentially other germline mutation in Apc, which results in these mice developing mediators. Prior studies in cell culture models have had many adenomas throughout the intestinal tract.6 This model has contradictory findings when examining the potential for an been widely used to study the biology of intestinal tumors and as interaction between these signaling cascades.12–17 To examine a valuable tool for chemoprevention studies. what effect mutations in APC and PIK3CA have on tumorigenesis, Genetic alterations in the phosphoinositide-3 kinase (PI3K) we have crossed the Min mouse with the FCPIK3ca* (FC13K1) signaling pathway are the most common mutations found in mouse. This cross results in a murine model with the loss of one cancer.7 Oncogenic mutations of PIK3CA are important in multiple allele of APC throughout the intestine and the expression of a 1Division of Hematology and Oncology, Department of Medicine, University of Wisconsin, Madison, WI, USA; 2Department of Oncology, University of Wisconsin, Madison, WI, USA; 3Division of Gastroenterology and Hepatology, Department of Medicine, University of Wisconsin, Madison, WI, USA; 4Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, WI, USA; 5Promega Corporation, Madison, WI, USA; 6Department of Pathology and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA and 7Department of Radiology, University of Wisconsin, Madison, WI, USA. Correspondence: Professor RB Halberg, Department of Medicine, University of Wisconsin, Clinical Science Center, 600 Highland Avenue, K4/532, Madison, WI 53792, USA. E-mail: [email protected] Received 25 January 2013; revised 8 March 2013; accepted 14 March 2013; published online 27 May 2013 PIK3CA and APC mutations are synergistic DA Deming et al 2246 Figure 1. FC13K1ApcMin/ þ mice become moribund by 52 days of age on average due to obstructive enteropathy or anemia. At necropsy, large proximal colon cancers result in distention of the cecum and small intestine (a) compared with control (b). These tumors are associated with enlarged mesenteric adenopathy (c). In addition, an impressive vascular supply is noted supplying tumors in the colon (c) and distal small intestine (d). The colon was removed and split lengthwise demonstrating a large flat proximal colon cancer and other smaller tumors in the colon (e). The distal small intestine was also resected and split lengthwise revealing multiple large tumors (f). The mesentery was also examined closely following removal of the colon and small intestine. Hyperplasia of the lymphatic tissue was seen in all mice (c, g). In some mice, tumor deposits were seen in the mesenteric adipose tissue (g, h) or within the lymphatic tissue (g, i). Size bars: (g) ¼ 2 mm; (h, i) ¼ 1 mm. (h, i) Enlargements of the boxes in (g). Oncogene (2014) 2245 – 2254 & 2014 Macmillan Publishers Limited PIK3CA and APC mutations are synergistic DA Deming et al 2247 dominant active PI3K (3K1) in the distal small intestine and colon Tumor development and progression are mediated by the due to the expression of Cre under the control of the fatty acid expression of the dominant active form of PI3K binding protein-1 promoter (FC1). Here, we demonstrate increased Expression of the constitutively active PI3K in the tumors of FC13K1 tumor multiplicity, size and a more aggressive and poorly mice has previously been shown to activate the PI3K signaling differentiated phenotype as a consequence of synergy between cascade.10 In FC13K1ApcMin/ þ mice, all tumors in the distal small APC and PIK3CA mutations. and large intestine, regardless of morphology, demonstrate the presence of p110* and activation of the PI3K signaling pathway (Figures 2–4), including elevated phosphorylation of AKT com- pared with tumors from ApcMin/ þ mice (Figure 2c). These RESULTS observations confirm that the transgene was transcribed and Expression of a dominantly active PI3K in the setting of allelic translated in the colon of FC13K1ApcMin/ þ mice and that its loss of Apc results in increased tumor multiplicity and increased expression resulted in increased downstream activation of the tumor size PI3K/AKT/MTOR pathway. FC13K1ApcMin/ þ mice were dissected once moribund with age- matched control littermates (Figure 1; 1 denotes carrier and 0 þ denotes non-carrier for FC and 3K; denotes wild type for Apc). Differences in tumor morphology result from the expression of the The majority of mice developed massive proximal colon cancers dominant active form of PI3K in the setting of allelic loss of Apc in resulting in obstruction of the lumen (Figure 1a). These tumors the intestine were associated with an impressive vascular supply and hyper- Tumors with multiple distinct morphologies develop in the plastic lymphatic tissue (Figures 1c and d). Tumors are seen in the FC13K1ApcMin/ þ mice (Figure 3; Supplementary Figures S1 and colon and distal small intestine (Figures 1e and f). In some S2). The flat lesions, previously described in the FC13K1 mice, are instances, metastatic lesions were noted in the mesenteric present (Figure 3a).10 These flat lesions are moderately lymphatic and adipose tissue (Figures 1g–i). No evidence of liver differentiated invasive mucinous adenocarcinomas that arise in or lung metastases was identified. A total of 61 mice were evaluated for the presence of intestinal tumors, including 18 FC13K1ApcMin/ þ mice, 17 FC03K1ApcMin/ þ 1 0 Min/ þ 0 0 Min/ þ ab10 5 mice, 6 FC 3K Apc mice, 9 FC 3K Apc mice and 11 S1-S2 FC13K1Min 1 1 þ / þ 9 FC 3K Apc mice (Supplementary Table S1). The average age of S3-S4 Min control 4 FC13K1ApcMin/ þ mice at necropsy was 52 days old. Mice appeared 8 Cecum-colon well until they became moribund from obstructive enteropathy 7 relating to large obstructing colon cancers or secondary to anemia 6 3 from bleeding intestinal tumors. 5 Tumor multiplicity was significantly increased in each section of 4 2 the intestine where the activated PI3K was expressed in the 3 setting of allelic loss of Apc (Figure 2).
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