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Preclinical Models to Study Obesity and Breast Cancer in Females: Considerations, Caveats, and Tools

Journal of Mammary Gland Biology and Neoplasia volume 25, pages 237–253 (2020)Cite this article

Abstract

Obesity increases the risk for breast cancer and is associated with poor outcomes for cancer patients. A variety of rodent models have been used to investigate these relationships; however, key differences in experimental approaches, as well as unique aspects of rodent physiology lead to variability in how these valuable models are implemented. We combine expertise in the development and implementation of preclinical models of obesity and breast cancer to disseminate effective practices for studies that integrate these fields. In this review, we share, based on our experience, key considerations for model selection, highlighting important technical nuances and tips for use of preclinical models in studies that integrate obesity with breast cancer risk and progression. We describe relevant mouse and rat paradigms, specifically highlighting differences in breast tumor subtypes, estrogen production, and strategies to manipulate hormone levels. We also outline options for diet composition and housing environments to promote obesity in female rodents. While we have applied our experience to understanding obesity-associated breast cancer, the experimental variables we incorporate have relevance to multiple fields that investigate women’s health.

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Data Availability

The data generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

ER:

Estrogen receptor

PR:

Progesterone receptor

HER2/ERBB2:

Human epidermal growth factor receptor 2

TN:

Triple negative

HR:

Hormone receptor

BMI:

Body mass index

PDX:

Patient derived xenograft

MNU:

1-methyl-1-nitrosourea

DMBA:

7,12-dimethylbenzathracene

MMTV:

Mouse mammary tumor virus

WAP:

Whey acidic promoter

PyMT:

Polyoma-virus middle T antigen

DIO:

Diet-induced obesity

DIOX:

Diet-induced obesity/xenograft

MDST:

Mouse-derived syngeneic transplant

NSG:

NOD-SCID (non-obese diabetic, severe combined immunodeficient) IL2R-gamma

PMBC:

Peripheral blood mononuclear cell

OVX:

Ovariectomy

DEXA:

Dual-energy x-ray absorptiometry

HF:

High fat

HFHS:

High fat/high sucrose

LFHS:

Low fat/high sucrose

LFLS:

Low fat/low sucrose

HOMA-IR:

Homeostatic model assessment of insulin resistance

OR:

Obesity-resistant

OP:

Obesity-prone

NK:

Natural killer

VCD:

4-vinylcyclohexene diepoxide

E2:

17ß-estradiol

qMR:

Quantitative magnetic resonance

NHANES:

National Health and Nutrition Examination Survey

PBMC:

Peripheral blood mononuclear cell

SEM:

Standard error of the mean

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Acknowledgments

Development of these models was a team effort, and we are incredibly grateful to the members of the ‘Fat Rat’ team, who were instrumental in developing and characterizing these models. This includes: Drs. Paul MacLean, Pepper Schedin, Ann Thor, Steven Anderson, and members of each of their labs. We are equally grateful to the skilled research technicians who ensured the success of the many studies in mice and rats that contributed to this work. Summary figures were created using BioRender.com.

Funding

This work was supported by the NIH R00CA169430 (Giles), R01CA241156 (Wellberg), R01CA164166 (MacLean), Colorado Nutrition Obesity Research Center Metabolic Phenotyping Core and Pilot Grant Program P30DK48520, TREC Training Workshop R25CA203650 (Giles and Wellberg), KL2TR002534 (Wellberg), the Komen Foundation CCR17483321 (Wellberg), and seed grants from the University of Colorado’s Center for Women’s Health Research (Giles and Wellberg).

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  1. Erin D. Giles and Elizabeth A. Wellberg contributed equally to this work.

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  1. Department of Nutrition, Texas A&M University, College Station, TX, USA

    Erin D. Giles

  2. Department of Pathology, University of Oklahoma Health Science Center, Stephenson Cancer Center, Harold Hamm Diabetes Center, Oklahoma City, OK, USA

    Elizabeth A. Wellberg

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  1. Erin D. Giles
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  2. Elizabeth A. Wellberg
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EDG and EAW contributed equally to this manuscript. Both authors contributed to the conception of the work and the acquisition, analysis, and interpretation of data. Both authors contributed to the intellectual content and writing of this paper and have approved the version to be published. Both EDG and EAW assume accountability for all aspects of the work and will ensure that any questions related to the accuracy or integrity of the work are appropriately investigated and resolved.

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Correspondence to Erin D. Giles.

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All animal work was approved by Texas A&M and/or University of Colorado Institutional Animal Care and Use Committees.

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Giles, E.D., Wellberg, E.A. Preclinical Models to Study Obesity and Breast Cancer in Females: Considerations, Caveats, and Tools. J Mammary Gland Biol Neoplasia 25, 237–253 (2020). https://doi.org/10.1007/s10911-020-09463-2

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