Background: Compelling evidence from numerous epidemiological studies worldwide shows that high-sugar diets are associated with increased breast cancer risk, but the data is not wholly consistent and the molecular mechanisms remain unclear. One proposed mechanism for the role of sugar in cancer development involves inflammation. Bioactive lipids, especially cyclooxygenases and lipoxygenases (LOXs) metabolites of arachidonic acid, are known to be involved in inflammation and cancers. Here we examined the effect of sucrose enriched diet in the development of primary and metastatic breast tumor and relevant molecular mechanism primarily focusing on 12-LOX pathway. Methods: Mice bearing three different types of breast tumors were fed with sucrose-enriched diets, and the primary tumors and lung metastasis were measured. The levels of 12- LOX protein expression and its arachidonate metabolite 12-HETE were determined in both tumor tissues from the mice and breast cancer cells in vitro. Results: A diet with 125 g/kg sucrose, a concentration equivalent to the average sugar consumption of American population (70 lb/person/year), notably shortened the breast tumorigenesis in MMTV-ErbB2/neu mice with increase of tumor incidence by 77%. Sucrose enriched-diets (125 g/kg) promoted the development of primary breast tumors in mice bearing mouse breast cancer 4T1 cells with an average tumor weight of 389.4±64.2 mg in the control animals vs. 534.0±90.5 mg in sucrose fed animals. The tumor weight was increased by 2.2-fold in mice injected with human triple negative breast cancer MDA-MB-231 cells upon sucrose diet feeding. Further, sucrose diet (125 g/kg) potentiated lung metastasis of 4T1 mouse mammary tumor evidenced by increasing the average numbers of lung nodules per mouse from 6.6±2.2 in control group to 13.0±5.0 in 125 g/kg sucrose group. The increased tumorigenicity of sucrose appears to be consistently associated with up-regulation of 12-LOX protein expression and 12-HETE production within the tumor tissues across the three breast tumorigenesis models. Additionally, 12-LOX and 12-HETE were induced in the glucose (30 mM) treated MDA-MB-231 cells and 12-HETE promoted MDA-MB-231 cell growth, invasion and migration. Proliferation of MDA-MB-231 cells cultured in 3-D matrigel was stimulated by glucose treatment, which was abrogated with the presence of 12-LOX inhibitor, Baicalein. Conclusion: Our data provides a strong evidence that added sugar (sucrose) accelerates the development of breast cancer partially through up-regulating expression of 12-LOX and production of 12-HETE. Therefore, dietary sugar induced 12-LOX signaling may play an important role in increased incidence for breast cancer that is associated with a high-carbohydrate diet and could be a promising target for intervention and risk-reducing strategies for breast cancer.
Citation Format: Yan Jiang, Yong Pan, Patrea R. Rhea, Lin Tan, Mihai Gagea-Iurascu, Lorenzo Cohen, Peiying Yang. Dietary sugar induces tumorigenesis in mammary gland partially through 12 lipoxygenase pathway. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3735. doi:10.1158/1538-7445.AM2015-3735