Abstract
Growing evidence indicates that adiposity is associated with breast cancer risk and negatively affects breast cancer recurrence and survival, a paracrine role of mammary adipose tissue being very likely in this process. In contrast to other adipose depots, occurrence of a sub-inflammatory state of mammary adipose tissue defined by dying adipocytes surrounded by macrophages forming crown-like structures in overweight and obese subjects, remains only partially described. In a general population of breast cancer patients (107 patients) mostly undergoing breast-conserving surgery, we found a positive association between patient’s body composition, breast adipocytes size, and presence of crown-like structures in mammary adipose tissue close to the tumor. Overweight (BMI: 25.0–29.9 kg/m2) and obese (BMI ≥ 30.0 kg/m2) patients have 3.2 and 6.9 times higher odds ratio of crown-like structures respectively, compared with normal weight patients. The relatively small increase in adipocyte size in crown-like structures positive vs. negative patients suggests that mammary adipose tissue inflammation might occur early during hypertrophy. Our results further highlight that body mass index is an adequate predictor of the presence of crown-like structures in mammary adipose tissue among postmenopausal women, whereas in premenopausal women truncal fat percentage might be more predictive, suggesting that mammary adipose tissue inflammation is more likely to occur in patients exhibiting visceral obesity. Finally, the presence of crown-like structures was positively associated with systemic markers such as the Triglyceride/High-density lipoprotein-cholesterol ratio serum C-reactive protein and glucose/(HbA1c) glycated Haemoglobin. These compelling results demonstrate that excess adiposity, even in overweight patients, is associated with mammary adipose tissue inflammation, an event that could contribute to breast cancer development and progression.
Highlights
Our results further highlight that BMI is an adequate predictor of the presence of CLS in mammary adipose tissue (MAT) among postmenopausal women, whereas the measure of truncal fat percentage might be more predictive in premenopausal women
Our study underlines that CLS are present in overweight patients in accordance with the fact that a relatively small increase in adipocyte size is observed between CLS positive and negative patients, suggesting that this tissue might be prone to inflammation during hypertrophy
These compelling results demonstrate that excess adiposity is associated with MAT inflammation, a condition that could contribute to breast cancer development and progression in a paracrine manner
Summary
Growing evidence from both clinical and preclinical studies indicates that adiposity is associated with breast cancer risk,[1, 2] and may act as a negative prognostic factor influencing breast cancer recurrence and survival.[1,2,3] These observations have recently been supported in mechanistic studies, observing that adiposity-associated factors, such as hormones, lipids, adipokines, and pro-inflammatory mediators are associated with breast cancer development and progression.[4, 5]Accumulating studies point to a role of mammary adipose tissue (MAT) adjacent to the tumors in breast cancer development and progression, as adipose tissue (AT) represents a major component of the breast tumor microenvironment.[6, 7] We and others have demonstrated that a bidirectional crosstalk takes place between breast cancer cells and tumor-surrounding AT.[8,9,10,11,12,13]Tumor-surrounding adipocytes may stimulate the aggressiveness of cancer cells by secreting extracellular matrix such as collagen VI and its fragment endotrophin,[11, 12] matrix metalloproteases,[13] chemokines,[10] and pro-inflammatory cytokines such as Interleukin-6 (IL6).[14]. Growing evidence from both clinical and preclinical studies indicates that adiposity is associated with breast cancer risk,[1, 2] and may act as a negative prognostic factor influencing breast cancer recurrence and survival.[1,2,3] These observations have recently been supported in mechanistic studies, observing that adiposity-associated factors, such as hormones, lipids, adipokines, and pro-inflammatory mediators are associated with breast cancer development and progression.[4, 5]. Accumulating studies point to a role of mammary adipose tissue (MAT) adjacent to the tumors in breast cancer development and progression, as adipose tissue (AT) represents a major component of the breast tumor microenvironment.[6, 7] We and others have demonstrated that a bidirectional crosstalk takes place between breast cancer cells and tumor-surrounding AT.[8,9,10,11,12,13]. IL-6 is an important growth factor for estrogen receptor-α (ERα)-positive breast cancer, and elevated serum IL-6 is associated with poor prognosis.[15, 16] These results strongly support the innovative concept that adipocytes may participate in a highly complex cycle orchestrated by cancer cells to support tumor initiation, growth, and metastasis, possibly amplified in overweight and obese breast cancer patients
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