Liza Makowski1, Chunxiao Zhou2, Yan Zhong2, Pei Fen Kuan3, Cheng Fan4, Brante P Sampey5, Megan Difurio6, Victoria L Bae-Jump7. 1. Department of Nutrition, University of North Carolina, Chapel Hill, NC, USA; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA. 2. Division of Gynecologic Oncology, University of North Carolina, Chapel Hill, NC, USA. 3. Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA; Department of Biostatistics, University of North Carolina, Chapel Hill, NC, USA. 4. Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA. 5. Metabolon, Inc., Durham, NC, USA. 6. Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA. 7. Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA; Division of Gynecologic Oncology, University of North Carolina, Chapel Hill, NC, USA. Electronic address: victoria_baejump@med.unc.edu.
Abstract
OBJECTIVES: Obesity is associated with increased risk and worse outcomes for ovarian cancer. Thus, we examined the effects of obesity on ovarian cancer progression in a genetically engineered mouse model of serous ovarian cancer. METHODS: We utilized a unique serous ovarian cancer mouse model that specifically deletes the tumor suppressor genes, Brca1 and p53, and inactivates the retinoblastoma (Rb) proteins in adult ovarian surface epithelial cells, via injection of an adenoviral vector expressing Cre (AdCre) into the ovarian bursa cavity of adult female mice (KpB mouse model). KpB mice were subjected to a 60% calories-derived from fat in a high fat diet (HFD) versus 10% calories from fat in a low fat diet (LFD) to mimic diet-induced obesity. Tumors were isolated at 6 months after AdCre injection and evaluated histologically. Untargeted metabolomic and gene expression profiling was performed to assess differences in the ovarian tumors from obese versus non-obese KpB mice. RESULTS: At sacrifice, mice on the HFD (obese) were twice the weight of mice on the LFD (non-obese) (51g versus 31g, p=0.0003). Ovarian tumors were significantly larger in the obese versus non-obese mice (3.7cm(2) versus 1.2cm(2), p=0.0065). Gene expression and metabolomic profiling indicated statistically significant differences between the ovarian tumors from the obese versus non-obese mice, including metabolically relevant pathways.
OBJECTIVES: Obesity is associated with increased risk and worse outcomes for ovarian cancer. Thus, we examined the effects of obesity on ovarian cancer progression in a genetically engineered mouse model of serous ovarian cancer. METHODS: We utilized a unique serous ovarian cancer mouse model that specifically deletes the tumor suppressor genes, Brca1 and p53, and inactivates the retinoblastoma (Rb) proteins in adult ovarian surface epithelial cells, via injection of an adenoviral vector expressing Cre (AdCre) into the ovarian bursa cavity of adult female mice (KpB mouse model). KpB mice were subjected to a 60% calories-derived from fat in a high fat diet (HFD) versus 10% calories from fat in a low fat diet (LFD) to mimic diet-induced obesity. Tumors were isolated at 6 months after AdCre injection and evaluated histologically. Untargeted metabolomic and gene expression profiling was performed to assess differences in the ovarian tumors from obese versus non-obese KpB mice. RESULTS: At sacrifice, mice on the HFD (obese) were twice the weight of mice on the LFD (non-obese) (51g versus 31g, p=0.0003). Ovarian tumors were significantly larger in the obese versus non-obese mice (3.7cm(2) versus 1.2cm(2), p=0.0065). Gene expression and metabolomic profiling indicated statistically significant differences between the ovarian tumors from the obese versus non-obese mice, including metabolically relevant pathways.
Authors: James C Pavelka; Rebecca S Brown; Beth Y Karlan; Ilana Cass; Ronald S Leuchter; Leo D Lagasse; Andrew J Li Journal: Cancer Date: 2006-10-01 Impact factor: 6.860
Authors: Ludmila Szabova; Chaoying Yin; Sujata Bupp; Theresa M Guerin; Jerome J Schlomer; Deborah B Householder; Maureen L Baran; Ming Yi; Yurong Song; Wenping Sun; Jonathan E McDunn; Philip L Martin; Terry Van Dyke; Simone Difilippantonio Journal: Cancer Res Date: 2012-05-22 Impact factor: 12.701
Authors: Shoshana Yakar; Nomeli P Nunez; Patricia Pennisi; Pnina Brodt; Hui Sun; Lucia Fallavollita; Hong Zhao; Louis Scavo; Ruslan Novosyadlyy; Naamit Kurshan; Bethel Stannard; Joyce East-Palmer; Nicole C P Smith; Susan N Perkins; Robin Fuchs-Young; J Carl Barrett; Stephen D Hursting; Derek LeRoith Journal: Endocrinology Date: 2006-09-07 Impact factor: 4.736
Authors: Douglas A Hosack; Glynn Dennis; Brad T Sherman; H Clifford Lane; Richard A Lempicki Journal: Genome Biol Date: 2003-09-11 Impact factor: 13.583
Authors: F Lubin; A Chetrit; L S Freedman; E Alfandary; Y Fishler; H Nitzan; A Zultan; B Modan Journal: Am J Epidemiol Date: 2003-01-15 Impact factor: 4.897
Authors: Hui Guo; Weimin Kong; Lu Zhang; Jianjun Han; Leslie H Clark; Yajie Yin; Ziwei Fang; Wenchuan Sun; Jiandong Wang; Timothy P Gilliam; Douglas Lee; Liza Makowski; Chunxiao Zhou; Victoria L Bae-Jump Journal: Am J Cancer Res Date: 2019-10-01 Impact factor: 6.166
Authors: Yueying Liu; Matthew N Metzinger; Kyle A Lewellen; Stephanie N Cripps; Kyle D Carey; Elizabeth I Harper; Zonggao Shi; Laura Tarwater; Annie Grisoli; Eric Lee; Ania Slusarz; Jing Yang; Elizabeth A Loughran; Kaitlyn Conley; Jeff J Johnson; Yuliya Klymenko; Lana Bruney; Zhong Liang; Norman J Dovichi; Bentley Cheatham; W Matthew Leevy; M Sharon Stack Journal: Cancer Res Date: 2015-11-16 Impact factor: 12.701
Authors: Monjri M Shah; Britt K Erickson; Tasnia Matin; Gerald McGwin; Jovana Y Martin; Laura Becca Daily; Daniel Pasko; Christen W Haygood; Janelle M Fauci; Charles A Leath Journal: Gynecol Oncol Date: 2014-09-16 Impact factor: 5.482
Authors: C M Nagle; S C Dixon; A Jensen; S K Kjaer; F Modugno; A deFazio; S Fereday; J Hung; S E Johnatty; P A Fasching; M W Beckmann; D Lambrechts; I Vergote; E Van Nieuwenhuysen; S Lambrechts; H A Risch; M A Rossing; J A Doherty; K G Wicklund; J Chang-Claude; M T Goodman; R B Ness; K Moysich; F Heitz; A du Bois; P Harter; I Schwaab; K Matsuo; S Hosono; E L Goode; R A Vierkant; M C Larson; B L Fridley; C Høgdall; J M Schildkraut; R P Weber; D W Cramer; K L Terry; E V Bandera; L Paddock; L Rodriguez-Rodriguez; N Wentzensen; H P Yang; L A Brinton; J Lissowska; E Høgdall; L Lundvall; A Whittemore; V McGuire; W Sieh; J Rothstein; R Sutphen; H Anton-Culver; A Ziogas; C L Pearce; A H Wu; P M Webb Journal: Br J Cancer Date: 2015-07-07 Impact factor: 7.640
Authors: Jun He; Megan T Quintana; Jenyth Sullivan; Traci L Parry; Trisha J Grevengoed; Jonathan C Schisler; Joseph A Hill; Cecelia C Yates; Rudo F Mapanga; M Faadiel Essop; William E Stansfield; James R Bain; Christopher B Newgard; Michael J Muehlbauer; Yipin Han; Brian A Clarke; Monte S Willis Journal: Cardiovasc Diabetol Date: 2015-08-05 Impact factor: 9.951