TY - JOUR
T1 - Macrophages Upregulate Estrogen Receptor Expression in the Model of Obesity-Associated Breast Carcinoma
AU - Nahmias Blank, Daniela
AU - Hermano, Esther
AU - Sonnenblick, Amir
AU - Maimon, Ofra
AU - Rubinstein, Ariel M.
AU - Drai, Emmy
AU - Maly, Bella
AU - Vlodavsky, Israel
AU - Popovtzer, Aron
AU - Peretz, Tamar
AU - Meirovitz, Amichay
AU - Elkin, Michael
N1 - Publisher Copyright:
© 2022 by the authors.
PY - 2022/9/1
Y1 - 2022/9/1
N2 - Breast cancer (BC) and obesity are two heterogeneous conditions with a tremendous impact on health. BC is the most commonly diagnosed neoplasm and the leading cause of cancer-related mortality among women, and the prevalence of obesity in women worldwide reaches pandemic proportions. Obesity is a significant risk factor for both incidence and worse prognosis in estrogen receptor positive (ER+) BC. Yet, the mechanisms underlying the association between excess adiposity and increased risk/therapy resistance/poorer outcome of ER+, but not ER−negative (ER−), BC are not fully understood. Tumor-promoting action of obesity, predominantly in ER + BC patients, is often attributed to the augmented production of estrogen in ‘obese’ adipose tissue. However, in addition to the estrogen production, expression levels of ER represent a key determinant in hormone-driven breast tumorigenesis and therapy response. Here, utilizing in vitro and in vivo models of BC, we show that macrophages, whose adverse activation by obesogenic substances is fueled by heparanase (extracellular matrix-degrading enzyme), are capable of upregulating ER expression in tumor cells, in the setting of obesity-associated BC. These findings underscore a previously unknown mechanism through which interplay between cellular/extracellular elements of obesity-associated BC microenvironment influences estrogen sensitivity—a critical component in hormone-related cancer progression and resistance to therapy.
AB - Breast cancer (BC) and obesity are two heterogeneous conditions with a tremendous impact on health. BC is the most commonly diagnosed neoplasm and the leading cause of cancer-related mortality among women, and the prevalence of obesity in women worldwide reaches pandemic proportions. Obesity is a significant risk factor for both incidence and worse prognosis in estrogen receptor positive (ER+) BC. Yet, the mechanisms underlying the association between excess adiposity and increased risk/therapy resistance/poorer outcome of ER+, but not ER−negative (ER−), BC are not fully understood. Tumor-promoting action of obesity, predominantly in ER + BC patients, is often attributed to the augmented production of estrogen in ‘obese’ adipose tissue. However, in addition to the estrogen production, expression levels of ER represent a key determinant in hormone-driven breast tumorigenesis and therapy response. Here, utilizing in vitro and in vivo models of BC, we show that macrophages, whose adverse activation by obesogenic substances is fueled by heparanase (extracellular matrix-degrading enzyme), are capable of upregulating ER expression in tumor cells, in the setting of obesity-associated BC. These findings underscore a previously unknown mechanism through which interplay between cellular/extracellular elements of obesity-associated BC microenvironment influences estrogen sensitivity—a critical component in hormone-related cancer progression and resistance to therapy.
KW - breast cancer
KW - estrogen
KW - estrogen receptor α
KW - heparanase
KW - macrophages
KW - obesity
UR - http://www.scopus.com/inward/record.url?scp=85138336130&partnerID=8YFLogxK
U2 - 10.3390/cells11182844
DO - 10.3390/cells11182844
M3 - Article
C2 - 36139419
AN - SCOPUS:85138336130
SN - 2073-4409
VL - 11
JO - Cells
JF - Cells
IS - 18
M1 - 2844
ER -