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.
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