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.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZES1-LKB-V (02))
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Reinlib, Leslie J
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University of North Carolina Chapel Hill
Public Health & Prev Medicine
Schools of Public Health
Chapel Hill
United States
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Chollet-Hinton, Lynn; Puvanesarajah, Samantha; Sandhu, Rupninder et al. (2018) Stroma modifies relationships between risk factor exposure and age-related epithelial involution in benign breast. Mod Pathol 31:1085-1096
Sun, Xuezheng; Shan, Yue; Li, Quefeng et al. (2018) Intra-individual Gene Expression Variability of Histologically Normal Breast Tissue. Sci Rep 8:9137
Sun, Xuezheng; Stewart, Delisha A; Sandhu, Rupninder et al. (2018) Correlated metabolomic, genomic, and histologic phenotypes in histologically normal breast tissue. PLoS One 13:e0193792
Sun, Xuezheng; Nichols, Hazel B; Tse, Chiu-Kit et al. (2016) Association of Parity and Time since Last Birth with Breast Cancer Prognosis by Intrinsic Subtype. Cancer Epidemiol Biomarkers Prev 25:60-7
Troester, Melissa A; Hoadley, Katherine A; D'Arcy, Monica et al. (2016) DNA defects, epigenetics, and gene expression in cancer-adjacent breast: a study from The Cancer Genome Atlas. NPJ Breast Cancer 2:16007
Robinson, Whitney R; Nichols, Hazel B; Tse, Chiu Kit et al. (2016) Associations of Premenopausal Hysterectomy and Oophorectomy With Breast Cancer Among Black and White Women: The Carolina Breast Cancer Study, 1993-2001. Am J Epidemiol 184:388-99
Sandhu, Rupninder; Chollet-Hinton, Lynn; Kirk, Erin L et al. (2016) Digital histologic analysis reveals morphometric patterns of age-related involution in breast epithelium and stroma. Hum Pathol 48:60-8
Blackmon, Richard L; Sandhu, Rupninder; Chapman, Brian S et al. (2016) Imaging Extracellular Matrix Remodeling In Vitro by Diffusion-Sensitive Optical Coherence Tomography. Biophys J 110:1858-1868
Casbas-Hernandez, Patricia; Sun, Xuezheng; Roman-Perez, Erick et al. (2015) Tumor intrinsic subtype is reflected in cancer-adjacent tissue. Cancer Epidemiol Biomarkers Prev 24:406-14
Oldenburg, Amy L; Yu, Xiao; Gilliss, Thomas et al. (2015) Inverse-power-law behavior of cellular motility reveals stromal-epithelial cell interactions in 3D co-culture by OCT fluctuation spectroscopy. Optica 2:877-885

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