Primary Topic: Basic Science
Dietary sugar induces breast tumorigenesis in murine models partially through 12-Lipoxygenase and immune modulation
Peiying Yang, PhD; Yan Jiang, PhD; Patrea Rhea, BS; Mihai Gagea, DVM, PhD; Lorenzo Cohen, PhD, , Houston, TX, United States
Late Breaker: No
High added sugar consumption might be associated with increased breast cancer (BCa) risk, but the data is not consistent and the molecular mechanisms remain unclear. We examined the effect of sucrose-enriched diet in the development of primary and metastatic BCa, and relevant mechanisms.
MMTV-ErbB2/neu mice and mice bearing mouse mammary tumor 4T1 cells or human triple negative BCa MDA-MB-231 cells were used to evaluate the effect of sucrose diet in primary BCa development and metastasis. ALOX-12 knockdown MDA-MB-231 cells (CRISPR) and selective 12-LOX inhibitors were utilized to determine the role of 12-LOX on immune modulation and tumorigenesis.
A diet with 125 g/kg sucrose (equivalent to the average US sugar consumption) shortened breast tumorigenesis in MMTV-ErbB2/neu mice and promoted the development of BCa in mice bearing 4T1 cells and MDA-MB-231 cells. Further, sucrose diet significantly increased the numbers of lung nodules 2-fold in 4T1 animal models (p< 0.05). There was up-regulation of expression of 12-LOX protein and its metabolite, 12-HETE, within the tumor tissues across the three BCa models. When mice were fed with sucrose-enriched diets, the average mammary tumor weight in ALOX12 deficient MDA-MB-231 cell derived tumors were smaller than that of tumors derived from scramble MDA-MB-231 cells. Furthermore, sucrose-enriched diet led to 2-fold increases in protein and mRNA of monocyte chemoattractant protein 1 (MCP-1) in serum and tumor tissues of MMTV-ErbB2/neu mice and mice bearing 4T1 mammary tumors. Intriguingly, 12-HETE treatment concentration dependently increased MCP-1 in MDA-MB-231 cells whereas a selective 12-LOX inhibitor, ML355, inhibited the MCP-1 gene expression in MDA-MB-231 cells. Finally, 4T1 mammary tumors from sucrose diet had 2-fold higher inflammation score and infiltration of CD68+ cells (tumor associated macrophage) compared to that of starch control diet.
Our data provides evidence that added sugar accelerates the development of BCa through up-regulating expression of 12-LOX and immune modulation, especially MCP-1 pathway.