A1 Refereed original research article in a scientific journal
CC chemokine ligand 2 (CCL2) stimulates aromatase gene expression in mammary adipose tissue
Authors: Martínez-Chacón Gabriela, Yatkin Emrah, Polari Lauri, Dinç Deniz D, Peuhu Emilia, Hartiala Pauliina, Saarinen Niina, Mäkelä Sari
Publication year: 2021
Journal: FASEB Journal
Journal name in source: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Journal acronym: FASEB J
Article number: e21536
Volume: 35
Issue: 5
ISSN: 0892-6638
eISSN: 1530-6860
DOI: https://doi.org/10.1096/fj.201902485RRR
Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/56035334
Obesity is a risk factor for postmenopausal breast cancer. Obesity-related inflammation upregulates aromatase expression, the rate-limiting enzyme for estrogen synthesis, in breast adipose tissue (BAT), increasing estrogen production and cancer risk. The regulation of aromatase gene (CYP19A1) in BAT is complex, and the mechanisms linking obesity and aromatase dysregulation are not fully understood. An obesity-associated factor that could regulate aromatase is the CC chemokine ligand (CCL) 2, a pro-inflammatory factor that also activates signaling pathways implicated in CYP19A1 transcription. By using human primary breast adipose stromal cells (ASCs) and aromatase reporter (hARO-Luc) mouse mammary adipose explants, we demonstrated that CCL2 enhances the glucocorticoid-mediated CYP19A1 transcription. The potential mechanism involves the activation of PI.4 via ERK1/2 pathway. We also showed that CCL2 contributes to the pro-inflammatory milieu and aromatase expression in obesity, evidenced by increased expression of CCL2 and CYP19A1 in mammary tissues from obese hARO-Luc mice, and subcutaneous adipose tissue from obese women. In summary, our results indicate that postmenopausal obesity may promote CCL2 production in BAT, leading to exacerbation of the menopause-related inflammatory state and further stimulation of local aromatase and estrogens. These results provide new insights into the regulation of aromatase and may aid in finding approaches to prevent breast cancer.
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