Epidemiologic and experimental data have shown that a full term pregnancy reduces breast cancer risk. However, recent studies have suggested that while full term pregnancy does reduce risk for estrogen receptor and luminal breast cancers, pregnancy may actually increase risk of more aggressive basal-like breast cancers. There are complex relationships between age, race, parity, and obesity in observational human datasets making it difficult to translate these findings into public health messages - behavioral variables such as obesity and pregnancy are often correlated. Experimental studies using rodents have examined parity and obesity individually, but to date, the independent and joint effects of parity and obesity have not been dissected. This proposal will address this gap and will do so within the context of tumor heterogeneity, focusing specifically on the basal-like breast cancer subtype and the microenvironment changes that promote this breast cancer subtype during a vital window of susceptibility, the post partum period.
In aim 1, mouse models of basal-like and heterogeneous breast cancer will be used to study the tumor promoting effects of pregnancy and high fat diet. Endpoints will include tumor latency, tumor mass, gene expression and microRNA changes induced by pregnancy and/or obesity. Macrophage infiltration, an important variable in cancer progression and obesity pathogenesis will be characterized in the microenvironment of the tumors that form.
In aim 2, a co-culture system will be used to model the effects of obesity- and pregnancy-associated macrophage infiltration on basal-like and luminal breast cancers.
In aim 3, the investigators will conduct ancillary histology and expression studies on normal breast tissue from an ongoing study of breast microenvironment and utilize available gene expression and demographic information from that parent study in their analyses. Comparison of results across in vitro and in vivo systems and across species will help to identify the most important pathways and/or biomarkers that are differentially regulated by parity and obesity in the basal-like microenvironment.
In aim 4, the investigators will identify and address the knowledge needs of their target population and disseminate outreach tools through a network of national advocates.
|Sun, Xuezheng; Sandhu, Rupninder; Figueroa, Jonine D et al. (2014) Benign breast tissue composition in breast cancer patients: association with risk factors, clinical variables, and gene expression. Cancer Epidemiol Biomarkers Prev 23:2810-8|
|Robinson, Whitney R; Tse, Chiu Kit; Olshan, Andrew F et al. (2014) Body size across the life course and risk of premenopausal and postmenopausal breast cancer in Black women, the Carolina Breast Cancer Study, 1993-2001. Cancer Causes Control 25:1101-17|
|Makowski, Liza; Zhou, Chunxiao; Zhong, Yan et al. (2014) Obesity increases tumor aggressiveness in a genetically engineered mouse model of serous ovarian cancer. Gynecol Oncol 133:90-7|
|Freemerman, Alex J; Johnson, Amy R; Sacks, Gina N et al. (2014) Metabolic reprogramming of macrophages: glucose transporter 1 (GLUT1)-mediated glucose metabolism drives a proinflammatory phenotype. J Biol Chem 289:7884-96|
|Sundaram, Sneha; Freemerman, Alex J; Galanko, Joseph A et al. (2014) Obesity-mediated regulation of HGF/c-Met is associated with reduced basal-like breast cancer latency in parous mice. PLoS One 9:e111394|
|Sandhu, Rupninder; Rein, Jessica; D'Arcy, Monica et al. (2014) Overexpression of miR-146a in basal-like breast cancer cells confers enhanced tumorigenic potential in association with altered p53 status. Carcinogenesis 35:2567-75|
|Chhetri, Raghav K; Blackmon, Richard L; Wu, Wei-Chen et al. (2014) Probing biological nanotopology via diffusion of weakly constrained plasmonic nanorods with optical coherence tomography. Proc Natl Acad Sci U S A 111:E4289-97|
|Allicock, Marlyn; Graves, Neasha; Gray, Kathleen et al. (2013) African American women's perspectives on breast cancer: implications for communicating risk of basal-like breast cancer. J Health Care Poor Underserved 24:753-67|
|Sundaram, Sneha; Freemerman, Alex J; Johnson, Amy R et al. (2013) Role of HGF in obesity-associated tumorigenesis: C3(1)-TAg mice as a model for human basal-like breast cancer. Breast Cancer Res Treat 142:489-503|
|Oldenburg, Amy L; Chhetri, Raghav K; Cooper, Jason M et al. (2013) Motility-, autocorrelation-, and polarization-sensitive optical coherence tomography discriminates cells and gold nanorods within 3D tissue cultures. Opt Lett 38:2923-6|
Showing the most recent 10 out of 11 publications