A Sucrose-Enriched Diet Promotes Tumorigenesis in Mammary Gland in Part through the 12-Lipoxygenase Pathway

Abstract

Epidemiologic studies have shown that dietary sugar intake has a significant impact on the development of breast cancer. One proposed mechanism for how sugar impacts cancer development involves inflammation. In the current study, we investigated the impact of dietary sugar on mammary gland tumor development in multiple mouse models, along with mechanisms that may be involved. We found that sucrose intake in mice comparable with levels of Western diets led to increased tumor growth and metastasis, when compared with a nonsugar starch diet. This effect was ascribed in part to increased expression of 12-lipoxygenase (12-LOX) and its arachidonate metabolite 12-hydroxy-5Z,8Z,10E,14Z-eicosatetraenoic acid (12-HETE). We determined that fructose derived from the sucrose was responsible for facilitating lung metastasis and 12-HETE production in breast tumors. Overall, our data suggested that dietary sugar induces 12-LOX signaling to increase risks of breast cancer development and metastasis.

Figure 1. Dietary sucrose consistently increased mammary gland tumor growth in three mouse models

a. Tumor development in MMVT/neu mouse model. Top left: Tumor incidence at 6 months of age (n ≥12). Top right: Tumor weight. Bottom: H&E staining of normal mammary gland (left) and hyperplasia (middle) from control diet-fed mice and of adenomas from mice fed a 500-g/kg sucrose diet (right) at 3 months of age. b. Sucrose increased primary mammary gland tumor growth and metastasis of tumor in 4T1 cell-bearing mice (n≥3). Top left: Tumor weight. Top right: Lung tumor metastasis (micro and macro metastases combined). Bottom: Lung nodules in control (left), 62.5 g/kg sucrose-treated (middle) and 125 g/kg sucrose-treated (right) mice, showing that the tumor size was larger in the lungs from sugar treated mice compared that to the control mice. c. Tumor weight in MDA-MB-231 tumor-bearing mice (n≥5). Data are represented as mean ± s.e.m. *p<0.05.

Figure 2. Dietary sucrose altered 12-LOX protein expression and 12-HETE production in mouse tumors

a. MMTV/neu mouse tumors; b. 4T1 tumor-bearing mice; c. MDA-MB-231 tumor-bearing mice. Data are represented as mean ± s.e.m.

Figure 3. The sucrose diet promoted lung metastasis potentially due to the fructose

Dietary sucrose, fructose and glucose plus fructose diets all induced tumor weight and volume (a), metastasis (b) (macro metastasis only) and 12-HETE production (c) in breast tumors from the mice after treatment. Data are represented as mean ± s.e.m. *p<0.05; **p < 0.001.