Abstract
The role of adipocytes in cancer microenvironment has gained focus during the recent years. However, the characteristics of the cancer-associated adipocytes (CAA) in human breast cancer tissues and the underlying regulatory mechanism are not clearly understood. We reviewed pathology specimens of breast cancer patients to understand the morphologic characteristics of CAA, and profiled the mRNA and miRNA expression of CAA by using indirect co-culture system in vitro. The CAAs in human breast cancers showed heterogeneous topographic relationship with breast cancer cells within the breast microenvironment. The CAAs exhibited the characteristics of de-differentiation determined by their microscopic appearance and the expression levels of adipogenic markers. Additionally, the 3T3-L1 adipocytes indirectly co-cultured with breast cancer cells showed up-regulation of inflammation-related genes including Il6 and Ptx3. The up-regulation of IL6 in CAA was further observed in human breast cancer tissues. miRNA array of indirectly co-cultured 3T3-L1 cells showed increased expression of mmu-miR-5112 which may target Cpeb1. Cpeb1 is a negative regulator of Il6. The suppressive role of mmu-miR-5112 was confirmed by dual luciferase reporter assay, and mmu-miR-5112-treated adipocytes showed up-regulation of Il6. The transition of adipocytes into more inflammatory CAA resulted in proliferation-promoting effect in ER positive breast cancer cells such as MCF7 and ZR-75-1 but not in ER negative cells. In this study, we have determined the de-differentiated and inflammatory natures of CAA in breast cancer microenvironment. Additionally, we propose a miRNA-based regulatory mechanism underlying the process of acquiring inflammatory phenotypes in CAA.
Highlights
The association between the degree of obesity and the risk of breast cancer incidence has long been recognized
Recent studies have focused on the potential roles of adipocytes in the breast cancer microenvironment that may modulate the growth of the cancer cells [2, 3]
There are clinical studies suggesting that the degree of obesity is related to the risk of loco-regional recurrence in breast cancer patients suggesting a dynamic interactions between the local adipocytes and breast cancer cells in the tumor microenvironments [4, 5]
Summary
The association between the degree of obesity and the risk of breast cancer incidence has long been recognized. Recent studies have focused on the potential roles of adipocytes in the breast cancer microenvironment that may modulate the growth of the cancer cells [2, 3]. There are clinical studies suggesting that the degree of obesity is related to the risk of loco-regional recurrence in breast cancer patients suggesting a dynamic interactions between the local adipocytes and breast cancer cells in the tumor microenvironments [4, 5]. We aimed to characterize the CAA in human breast cancer tissues and to explore the regulatory mechanism of the CAA transition
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