Insulin-like growth factor binding protein-3 links obesity and breast cancer progression
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Tiffany Scully1, Sue M. Firth1, Carolyn D. Scott1, Hasanthi C. de Silva1, John E. Pintar2, Tailoi Chan-Ling3, Stephen M. Twigg4, Robert C. Baxter1
1Hormones and Cancer Laboratories, Kolling Institute, University of Sydney, Royal North Shore Hospital, Sydney, New South Wales 2065, Australia
2Department of Neuroscience and Cell Biology, Rutgers University, Robert Wood Johnson Medical School, New Brunswick, NJ 08854, USA
3Department of Anatomy, Bosch Institute, University of Sydney, Sydney, New South Wales 2006, Australia
4Charles Perkins Centre, Sydney Medical School, University of Sydney, Sydney, New South Wales 2006, Australia
Robert C. Baxter, email: [email protected]
Keywords: IGFBP-3, obesity, breast cancer, BP3KO mouse, T-cell
Received: January 21, 2016 Accepted: June 16, 2016 Published: July 18, 2016
Obesity is associated epidemiologically with poor breast cancer prognosis, but the mechanisms remain unclear. Since IGF binding protein-3 (IGFBP-3) influences both breast cancer growth and adipocyte maturation, it may impact on how obesity promotes breast oncogenesis. This study investigated the role of endogenous IGFBP-3 on the development of obesity and subsequently on breast tumor growth. Wild-type (WT) C57BL/6 or IGFBP-3-null (BP3KO) mice were fed a high-fat diet (HFD) or control chow-diet for 15 weeks before orthotopic injection with syngeneic EO771 murine breast cancer cells. When the largest tumor reached 1000 mm3, tissues and tumors were excised for analysis. Compared to WT, BP3KO mice showed significantly reduced weight gain and mammary fat pad mass (contralateral to tumor) in response to HFD, despite similar food intake. EO771 tumor weight and volume were increased by HFD and decreased by BP3KO. Despite differences in tumor size, tumors in BP3KO mice showed no differences from WT in the number of mitotically active (Ki67+) and apoptotic (cleaved caspase-3+) cells, but had greater infiltration of CD3+ T-cells. These data suggest that endogenous (circulating and/or stromal) IGFBP-3 is stimulatory to adipose tissue expansion and enhances mammary tumor growth in immune-competent mice, potentially by suppressing T-cell infiltration into tumors.
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