Crown-Like Structures in Breast Adipose Tissue: Early Evidence and Current Issues in Breast Cancer

Abstract

Obesity is an established risk factor for postmenopausal breast cancer and has been linked to worse breast cancer prognosis, most clearly for hormone receptor-positive breast cancers. The underlying mechanisms of the obesity–breast cancer association are not fully understood, but growing evidence points to the breast adipose tissue microenvironment playing an important role. Obesity-induced adipose tissue dysfunction can result in a chronic state of low-grade inflammation. Crown-like structures of the breast (CLS-B) were recently identified as a histologic marker of local inflammation. In this review, we evaluate the early evidence of CLS-B in breast cancer. Data from preclinical and clinical studies show that these inflammatory lesions within the breast are associated with local NF-κB activation, increased aromatase activity, and elevation of pro-inflammatory mediators (TNFα, IL-1β, IL-6, and COX-2-derived PGE2)—factors involved in multiple pathways of breast cancer development and progression. There is also substantial evidence from epidemiologic studies that CLS-B are associated with greater adiposity among breast cancer patients. However, there is insufficient evidence that CLS-B impact breast cancer risk or prognosis. Comparisons across studies of prognosis were complicated by differences in CLS-B evaluation and deficiencies in study design, which future studies should take into consideration. Breast adipose tissue inflammation provides a plausible explanation for the obesity–breast cancer association, but further study is needed to establish its role and whether markers such as CLS-B are clinically useful.

Local Biomarkers Involved in the Interplay between Obesity and Breast Cancer

“…Despite interpatient variability, breast cancer develops in an adipose-rich microenvironment, with the adipose tissue being critical for the normal development of the mammary gland [ 14 ]. Adipose tissue depots vary in function and composition in different regions of the body [ 13 ], but how the mammary adipose tissue differs from other adipose depots is not fully understood [ 8 ]. White adipose tissue is roughly divided into visceral and subcutaneous adipose tissue [ 8 ].…”

“…Adipose tissue depots vary in function and composition in different regions of the body [ 13 ], but how the mammary adipose tissue differs from other adipose depots is not fully understood [ 8 ]. White adipose tissue is roughly divided into visceral and subcutaneous adipose tissue [ 8 ]. Despite its unique tissue-specific functions, the adipose tissue in the breast is considered subcutaneous white adipose tissue [ 13 , 15 ].…”

“…In normal-weight conditions, the adipose tissue is rich in anti-inflammatory immune cells, such as M2 macrophages and regulatory T cells, and anti-inflammatory cytokines, such as interleukin 10 (IL-10) [ 17 ]. In obesity, the adipose tissue expands and changes the homeostasis of the adipose tissue, resulting in adipose tissue dysfunction with deregulated adipokine, cytokine, and growth factor secretion [ 8 , 17 ]. Oxygen demands exceed the supply, leading to hypoxic conditions, adipocyte cell death, and a shift towards a pro-inflammatory state [ 18 , 19 ].…”

“…The immune cell landscape changes with the invasion of the pro-inflammatory M1 macrophages and CD8 + T cells, among others [ 17 , 18 ]. The secretion of pro-inflammatory adipokines and cytokines, such as leptin, IL-1, IL-6, and tumor necrosis factor alpha (TNF-α), is also increased [ 8 , 17 ]. The pro-inflammatory state contributes to an increase in aromatase activity, hereby inducing elevated levels of estrogen [ 20 ].…”

“…Various mechanisms have been proposed by which obesity affects the development of breast cancer, where the majority of studies have focused on the systemic alterations associated with obesity [ 8 , 9 ]. Less is known about the role of the local alterations in the breast microenvironment.…”