Transition into inflammatory cancer-associated adipocytes in breast cancer microenvironment requires microRNA regulatory mechanism.
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.
Center for Medical Innovation, Seoul National University Hospital, Seoul, Korea.
Jiwoo
J
Lee
Center for Medical Innovation, Seoul National University Hospital, Seoul, Korea.
Bok Sil
BS
Hong
Department of Pathology, Seoul National University Hospital, Seoul, Korea.
Han Suk
HS
Ryu
Center for Medical Innovation, Seoul National University Hospital, Seoul, Korea.|Department of Surgery, Seoul National University College of Medicine, Seoul, Korea.
Han-Byoel
HB
Lee
Center for Medical Innovation, Seoul National University Hospital, Seoul, Korea.
Minju
M
Lee
Department of Pathology, Seoul National University Hospital, Seoul, Korea.
In Ae
IA
Park
Center for Medical Innovation, Seoul National University Hospital, Seoul, Korea.|Department of Surgery, Seoul National University College of Medicine, Seoul, Korea.
Jisun
J
Kim
Center for Medical Innovation, Seoul National University Hospital, Seoul, Korea.|Department of Surgery, Seoul National University College of Medicine, Seoul, Korea.|Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
Wonshik
W
Han
Center for Medical Innovation, Seoul National University Hospital, Seoul, Korea.|Department of Surgery, Seoul National University College of Medicine, Seoul, Korea.|Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
Dong-Young
DY
Noh
Center for Medical Innovation, Seoul National University Hospital, Seoul, Korea.|Department of Surgery, Seoul National University College of Medicine, Seoul, Korea.|Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
Hyeong-Gon
http://orcid.org/0000-0002-9981-0286
HG
Moon
D016475:3T3 Cells; D017667:Adipocytes / Q000473:pathology / Q000502:physiology*; D050156:Adipogenesis / Q000502:physiology; D000818:Animals; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D002097:C-Reactive Protein / Q000502:physiology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D018920:Coculture Techniques; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006801:Humans; D007249:Inflammation / Q000503:physiopathology; D015850:Interleukin-6 / Q000502:physiology; D051379:Mice; D035683:MicroRNAs / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D000683:Serum Amyloid P-Component / Q000502:physiology; D059016:Tumor Microenvironment / Q000502:physiology*; D000099153:Pentraxins
D002097:C-Reactive Protein; D015850:Interleukin-6; D035683:MicroRNAs; D000683:Serum Amyloid P-Component; D000099153:Pentraxins; C508600:IL6 protein, human