MRI reveals increased tumorigenesis following high fat feeding in a mouse model of triple‐negative breast cancer

Abstract

High animal fat consumption is associated with an increase in triple-negative breast cancer (TNBC) risk. Based on previous MRI studies demonstrating the feasibility of detecting very early non-palpable mammary cancers in simian virus 40 large T antigen (SV40TAg) mice, we examined the effect of dietary fat fed from weaning to young adulthood in this model of TNBC. Virgin female C3(1)SV40TAg mice (n = 16) were weaned at 3–4 weeks of age and then fed either a low fat diet (LFD) (n = 8, 3.7 kcal/g; 17.2% kcal from vegetable oil) or a high animal fat diet (HAFD) (n = 8, 5.3 kcal/g; 60% kcal from lard). After 8 weeks on the diet (12 weeks of age), fast spin echo MR images of inguinal mammary glands were acquired at 9.4 T. Following in vivo MRI, mice were sacrificed and inguinal mammary glands were excised and formalin fixed for ex vivo MRI. 3D volume-rendered MR images were then correlated with mammary gland histology to assess the glandular parenchyma and tumor burden. Using in vivo MRI, an average of 3.88 ± 1.03 tumors were detected per HAFD-fed mouse compared with an average of 1.25 ± 1.16 per LFD-fed mouse (p < 0.007). Additionally, the average tumor volume was significantly higher following HAFD feeding (0.53 ± 0.45 mm3) compared with LFD feeding (0.20 ± 0.08 mm3, p < 0.02). Analysis of ex vivo MR and histology images demonstrated that HAFD mouse mammary glands had denser parenchyma, irregular and enlarged ducts, dilated blood vessels, increased white adipose tissue, and increased tumor invasion. MRI and histological studies of the SV40TAg mice demonstrated that HAFD feeding also resulted in higher cancer incidence and larger mammary tumors. Unlike other imaging methods for assessing environmental effects on mammary cancer growth, MRI allows routine serial measurements and reliable detection of small cancers as well as accurate tumor volume measurements and assessment of the three-dimensional distribution of tumors over time.

Metabolically activated macrophages in mammary adipose tissue link obesity to triple-negative breast cancer

“…As previously reported (Mustafi et al, 2017), DIO increased the total tumor burden in C3(1)-TAg mice (Fig. 1D), and this increased burden was due, in part, to the presence of more tumors in obese mice ( Fig.…”

Magnetic resonance angiography reveals increased arterial blood supply and tumorigenesis following high fat feeding in a mouse model of triple‐negative breast cancer

“…Past MRI studies from this laboratory have demonstrated both an increase in the recruitment of arteries to cancerous mammary glands in SV40Tag transgenic mice with TNBC 22 and an increase in invasive mammary cancers due to a high fat diet in this mouse model. 12 Using serial MRI, this study confirms the increase and observes its pattern over 5 weeks, beginning the scans at an earlier time point to observe any changes in the mammary glands throughout the development of the cancer. Additionally, this study shows the corresponding increase in mammary gland volume, as well as blood volume in the mammary glands, using TOF MRI.…”

“…The mammary glands of HAFD-fed mice exhibited irregular and enlarged ducts, dilated blood vessels, and more mature white adipose tissue, while the mammary glands of LFD-fed mice exhibited fewer/smaller blood vessels, and more abundant brown adipose tissue. 12,25 The connection between high fat diet/obesity and breast cancer has been attributed in part to adipose tissue dysfunction. 26 The increase in blood volume and vascular density in the mammary glands of mice fed an HAFD as determined by MRI in this study has been corroborated with histological images using H&E staining.…”

“…Thus, the potential negative metabolic effects of obesity are eliminated and the effects of the HAFD on tumor growth can be studied without that confounding variable. 17 While past studies have demonstrated the impact of an HAFD on tumor burden, [6][7][8][9][10]12 results from these previous studies do not explain factors such as the timing of the onset of in situ cancer or the progression from in situ to invasive cancers. Most previous work focuses on ultrasound as an imaging method or uses only immunohistochemical analysis or gene expression profiling to test for changes ex vivo.…”

“…11 One potential explanation for this relationship is that consumption of an HAFD can result in inflammation that promotes the growth of mammary cancers. 12 Additionally, a study of mouse models with colon cancer determined a link between an HAFD and increased tumor angiogenesis due to an increase in angiogenesis-promoting growth factors such as VEGF and CD31, 13 but this linkage has not been investigated in breast cancer and no studies have utilized non-invasive imaging to track the progression of cancer and associated vasculature. This study is the first to non-invasively and serially track changes in in situ and invasive cancers and angiogenesis in a study of dietary manipulations with an HAFD.…”