Studies in humans and animals indicate that the origins of breast cancer likely occur early in development, especially during puberty, a time of rapid breast development. Animal studies show that pubertal diet and environmental exposures can increase mammary cancer susceptibility. Human and animal studies of breast cancer show inflammatory processes (IP) contribute to tumor proliferation and metastasis. Preliminary results in BALB/c mice show pubertal exposure to a high fat diet (HFD) increases pubertal mammary gland proliferation and DMBA-induced mammary tumorigenesis. The investigators will also show that pubertal exposure to HFD induces IP. Importantly, these effects occur without obesity. They hypothesize that HFD increases mammary gland proliferation and mammary tumorigenesis through induction of IP. IP are a necessary and key component of normal mammary gland development. The investigators recently identified a novel pathway linking progesterone (P) to regulation of IP during mammary gland development. They further hypothesize that P-induced RANKL expression in the mammary epithelium is critical in promoting normal IP by activating NFkB, a transcriptional regulator of proinflammatory gene products, and that RANKL is the central regulator of HFD-induced IP in the mammary gland. The investigators propose that the observed HFD-induced RANKL expression, subsequent IP activation through NFkB, and peri-epithelial infiltration of macrophages and eosinophils promote both mammary gland proliferation and tumorigenesis. They will test these hypotheses during normal pubertal mammary gland development, and during DMBA and p53-/- carcinogenesis in BALB/c mice fed control and HFD. The investigators will also test several experimental intervention strategies to overcome the negative effects of diet on inflammation, and on mammary cancer development. Understanding the regulation of IP in normal pubertal mammary gland development, as well as in carcinogenesis, may provide relevant information about how other environmental factors (i.e., endocrine disrupters, toxicants) may increase susceptibility to mammary cancer. With their community breast cancer advocacy partner, Michigan Breast Cancer Coalition, the investigators will translate and communicate their research findings to the concerned public.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01ES019434-04
Application #
8463533
Study Section
Special Emphasis Panel (ZES1-LKB-V (02))
Program Officer
Reinlib, Leslie J
Project Start
2010-09-01
Project End
2015-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
4
Fiscal Year
2013
Total Cost
$442,411
Indirect Cost
$153,915
Name
Michigan State University
Department
Physiology
Type
Schools of Medicine
DUNS #
193247145
City
East Lansing
State
MI
Country
United States
Zip Code
48824
Wang, Weizhong; Do, Han Ngoc; Aupperlee, Mark D et al. (2018) C/EBP? LIP and c-Jun synergize to regulate expression of the murine progesterone receptor. Mol Cell Endocrinol 477:57-69
Aupperlee, Mark D; Kariagina, Anastasia; Zaremba, Nicole et al. (2018) The Proliferative Response to p27 Down-Regulation in Estrogen Plus Progestin Hormonal Therapy is Lost in Breast Tumors. Transl Oncol 11:518-527
Zhu, Yirong; Aupperlee, Mark D; Haslam, Sandra Z et al. (2017) Pubertally Initiated High-Fat Diet Promotes Mammary Tumorigenesis in Obesity-Prone FVB Mice Similarly to Obesity-Resistant BALB/c Mice. Transl Oncol 10:928-935
Biro, Frank M; Pinney, Susan M; Schwartz, Richard C et al. (2017) Amphiregulin as a Novel Serum Marker of Puberty in Girls. J Pediatr Adolesc Gynecol 30:535-539
Aupperlee, Mark D; Zhao, Yong; Tan, Ying Siow et al. (2015) Puberty-specific promotion of mammary tumorigenesis by a high animal fat diet. Breast Cancer Res 17:138
Aupperlee, Mark D; Zhao, Yong; Tan, Ying Siow et al. (2014) Epidermal growth factor receptor (EGFR) signaling is a key mediator of hormone-induced leukocyte infiltration in the pubertal female mammary gland. Endocrinology 155:2301-13
Aupperlee, Mark D; Leipprandt, Jeffrey R; Bennett, Jessica M et al. (2013) Amphiregulin mediates progesterone-induced mammary ductal development during puberty. Breast Cancer Res 15:R44