Abstract
A major challenge to breast cancer research is the identification of alterations in the architecture and composition of the breast that are associated with breast cancer progression. The aim of the present investigation was to characterize the mammary adipose phenotype from Brca1 mutant mice in the expectation that this would shed light on the role of the mammary tissue environment in the early stages of breast tumorigenesis. We observed that histological sections of mammary tissue from adult Brca1 mutant mice abnormally display small, multilocular adipocytes that are reminiscent of brown adipose tissue (BAT) as compared to wildtype mice. Using a marker for BAT, the uncoupling protein 1 (UCP1), we demonstrated that these multilocular adipose regions in Brca1 mutant mice stain positive for UCP1. Transcriptionally, UCP1 mRNA levels in the Brca1 mutant mice were elevated greater than 50-fold compared to age-matched mammary glands from wildtype mice. Indeed, BAT has characteristics that are favorable for tumor growth, including high vascularity. Therefore, we also demonstrated that the multilocular brown adipose phenotype in the mammary fat pad of Brca1 mutant mice displayed regions of increased vascularity as evidenced by a significant increase in the protein expression of CD31, a marker for angiogenesis. This Brca1 mutant mouse model should provide a physiologically relevant context to determine whether brown adipose tissue can play a role in breast cancer development.
Highlights
The mammary gland undergoes a dynamic series of alterations in its architecture and morphology during normal development as well as the development of breast cancer [1,2,3,4]
We observed that the dense area in the mammary fat pad of Brca1 mutant mice had smaller, multilocular adipocytes that are histologically reminiscent of brown adipose tissue (BAT) (Figure 2b)
We found this multilocular BAT phenotype to be unique to the mammary fat pads of Brca1 mutant mice since we did not observe this phenotype in other adult wildtype mouse models examined
Summary
The mammary gland undergoes a dynamic series of alterations in its architecture and morphology during normal development as well as the development of breast cancer [1,2,3,4]. Breast cancer is thought to occur initially in mammary epithelial cells (MECs) [1,2]. While MECs that harbor mutations can often initiate breast tumorigenesis, studies have shown that the stromal microenvironment surrounding MECs can play a major role in tumor cell fate [5]. Studies have shown that this tissue environment can act as both a barrier to tumorigenesis by suppressing tumor growth or it can act as a permissive environment for tumor growth promoting MECs towards transformation and a malignant state [5]
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