Abnormal Mammary Adipose Tissue Environment of Brca1 Mutant Mice Show a Persistent Deposition of Highly Vascularized Multilocular Adipocytes

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.

Mammary alveolar epithelial cells convert to brown adipocytes in post‐lactating mice

“…Interestingly, loss of PPARγ—a transcription factor involved both in adipogenesis (Hallenborg et al, ) and alveologenesis (Jain et al, )—in mammary secretory epithelial cells creates a pro‐breast tumorigenic environment during mammary gland involution (Apostoli et al, ); the process may to some extent be related to impaired epithelial cell to white adipocyte transdifferentiation. MiR‐27a, an inhibitor of brown adipogenesis (Sun & Trajkovski, ), has been reported to promote breast cancer growth and metastasis in humans (Tang et al, ) and could be a factor involved in the still unknown relationship between brown fat and breast cancer progression that has been observed in some experimental models (Jones, Buelto, Tago, & Owusu‐Boaitey, ).…”

Increased Expression of Beige/Brown Adipose Markers from Host and Breast Cancer Cells Influence Xenograft Formation in Mice

“…Using 18 F-fluorodeoxyglucose (FDG) tracer and PET/CT imaging, a high prevalence of BAT activity was recently found in breast cancer patients when compared to weight-matched patients with other solid tumor malignancies (12). In addition, persistent deposition of brown adipocytes has been detected in the mammary glands of BRCA1 mutant mice (13). Increased BAT in the mammary glands of these mutant mice has been correlated with up-regulation of the angiogenic marker CD31 (13).…”

“…In addition, persistent deposition of brown adipocytes has been detected in the mammary glands of BRCA1 mutant mice (13). Increased BAT in the mammary glands of these mutant mice has been correlated with up-regulation of the angiogenic marker CD31 (13). Also, a recent study shows a higher browning of mammary fat close to malignant breast tumors when compared to those in the vicinity of benign lesions (37).…”

“…Although several lines of evidence have implicated white adipocytes in promoting aggressive breast tumor behavior, a few recent studies have also associated brown adipocytes with this complex disease (12, 13). Brown adipose tissue (BAT) has also been detected in postnatal mammary gland along with white adipocytes (14).…”

Brown Adipose Tissue at F-18 FDG PET/CT: Correlation of Metabolic Parameter with Demographics and Cancer-Related Characteristics in Cancer Patients

“…Local cross talk between brown adipocyte and tumor microenvironment as well as systemic effect of BAT-derivative cytokines may evolve cell proliferation and angiogenesis as the pivotal step in cancer Copyright © 2017, Iranian Journal of Radiology. This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/) which permits copy and redistribute the material just in noncommercial usages, provided the original work is properly cited U n c o r r e c t e d P r o o f growth (7)(8)(9)(10)(11). Association between brown adipose tissue and mutation in tumor suppressor genes has also been described (7,12).…”