Effects of High Fat Diet‐Induced Obesity on Mammary Tumorigenesis in the PyMT/MMTV Murine Model
Authors: Cranford Taryn Lindsey , Enos Reilly T , Velazquez Kandy T , Bader Jackie E , Davis J. Mark , Murphy E. Angela 
Published: November 2023

PURPOSE

Epidemiological studies provide strong evidence to suggest that obesity and associated adipose tissue (AT) inflammation are risk factors for breast cancer (BrCA). Obesity‐induced inflammation is thought to create favorable conditions for breast epithelial cell transformation, cancer cell proliferation and invasion, and tumor‐related angiogenesis. AT macrophages are thought to be a major player in this response. The purpose of this study was to examine mammary tumorigenesis in response to high fat diet (HFD) feedings in the PyMT mouse model of tumorigenesis, a model that presents morphological similarities with human BrCA. We also sought to examine the link between obesity, AT macrophages and tumorigenesis. The majority of studies investigating the relationship between HFD‐induced obesity and BrCA tumorigenesis have been performed in the FVB/N background, a strain traditionally shown to be HFD‐induced obesity resistant. Therefore, this study was performed in the C57Bl/6 background, a strain that is very susceptible to HFD‐induced obesity.

METHODS

Male PyMT/MMTV mice on a C57Bl/6 background were bred with female wild‐type (WT) mice to obtain female mice heterozygous for the PyMT transgene. Female WT littermates were included as a non‐disease control. WT and PyMT mice were fed either a HFD (60% kcal as fat) or a low fat diet (LFD) (11.5% kcal as fat) control diet for 16 wks beginning at 4 wks of age. Body weights (BW) were measured weekly for all groups and body composition was analyzed at the conclusion of the study in WT mice. Tumors were palpable beginning at 10 wks of treatment and measured weekly using calipers. Primary tumors, adjacent mammary gland, lungs and visceral fat pads were excised at necropsy, weighed and saved for further analysis. AT mRNA expression of macrophage markers (F4/80 and CD11c) were measured using RT‐qPCR analysis.

RESULTS

A significant main effect of HFD treatment on BW and visceral fat mass was detected (P<0.05). Chronic consumption of a HFD significantly increased primary mammary tumor growth and multiplicity with the mean tumor vol/mouse and mean tumor num/mouse determined at necropsy to be 1989±380 mm3 and 8.85±0.96 for LFD, and 3163±542 mm3 and 10.47±0.76 for HFD mice, respectively. HFD consumption significantly increased tumor burden (i.e. weight) with the mean/mouse to be 1599.7±206.9g for LFD and 2554.0±375.4g for HFD (P<0.05). A significant main effect of diet was observed for macrophage markers F4/80 and CD11c expression in the AT (P<0.05).

CONCLUSION

These findings support the epidemiological literature linking HFD‐induced obesity to mammary tumorigenesis; PyMT mice exposed to chronic HFD consumption developed increased adiposity, macrophage infiltration in the AT, and exacerbated mammary tumorigenesis. These data provide support for further development of this model to examine the mechanisms driving obesity‐enhanced breast cancer.

Support or Funding Information

This work was supported by grants from the National Institutes of Health (F31CA183458 to T.L.C. and R21CA167058, R21CA175636 & K01AT007824 to E.A.M.).