Insulin-like growth factor binding protein-3 links obesity and breast cancer progression

Abstract

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.

Obesity promotes resistance to anti-VEGF therapy in breast cancer by up-regulating IL-6 and potentially FGF-2

“…This point has also been raised recently by Scully et al . (80), who, similar to our study, observed only a mild increase in E0771 tumor growth in obese mice (and similar vascular phenotypes, as discussed below). They stated that differences in the duration of feeding, the type of diet, age, or menopausal status of the mice may explain the different observations in the literature.…”

“…In addition, E0771 tumor cell growth was only modestly accelerated in obese compared to lean mice, particularly in the early stages of tumor growth. Although studies using the same tumor model have shown a similar growth pattern (80), Chen et al . (81) and Kolb et al .…”

Enhancement of mammary tumour growth by IGFBP-3 involves impaired T cell accumulation

“…High tumoural expression of IGFBP-3 has also been associated with poorer prognosis (Yu et al 1996, Rocha et al 1997, Sheen-Chen et al 2009, which may in part be driven by oncogenic pathways activated by IGFBP-3 (Baxter 2014, Martin et al 2014. In a previous study utilising IGFBP-3 global knock-out (BP3KO) mice in conjunction with high fat feeding, we demonstrated that IGFBP-3 deficiency resulted in reduced mammary tumour growth, and this effect was ameliorated by high fat feeding (Scully et al 2016). As part of investigating how tumour growth is reduced in the absence of host IGFBP-3, tumours grown in BP3KO mice were observed to contain increased numbers of CD3 + T cells (Scully et al 2016).…”

“…Animal studies were approved by the Northern Sydney Local Health District Animal Care and Ethics Committee (Protocol 1305-003A) and were conducted as previously described (Scully et al 2016). Briefly, a colony of IGFBP-3 global knock-out (BP3KO) mice bred onto a C57BL/6 background (Ning et al 2006) was established at the Kolling Institute.…”

“…In a previous study utilising IGFBP-3 global knock-out (BP3KO) mice in conjunction with high fat feeding, we demonstrated that IGFBP-3 deficiency resulted in reduced mammary tumour growth, and this effect was ameliorated by high fat feeding (Scully et al 2016). As part of investigating how tumour growth is reduced in the absence of host IGFBP-3, tumours grown in BP3KO mice were observed to contain increased numbers of CD3 + T cells (Scully et al 2016). This observation suggested that IGFBP-3 influences tumoural T cell infiltration, a previously unknown property that might further implicate IGFBP-3 in the regulation of tumour progression.…”