Abstract:
:Obesity is a highly prevalent and modifiable breast cancer risk factor. While the role of obesity in fueling breast cancer progression is well established, the mechanisms linking obesity to breast cancer initiation are poorly understood. A hallmark of breast cancer initiation is the disruption of apical polarity in mammary glands. Here we show that mice with diet-induced obesity display mislocalization of Par3, a regulator of cellular junctional complexes defining mammary epithelial polarity. We found that epithelial polarity loss also occurs in a 3D coculture system that combines acini with human mammary adipose tissue, and establish that a paracrine effect of the tissue adipokine leptin causes loss of polarity by overactivation of the PI3K/Akt pathway. Leptin sensitizes non-neoplastic cells to proliferative stimuli, causes mitotic spindle misalignment, and expands the pool of cells with stem/progenitor characteristics, which are early steps for cancer initiation. We also found that normal breast tissue samples with high leptin/adiponectin transcript ratio characteristic of obesity have an altered distribution of apical polarity markers. This effect is associated with increased epithelial cell layers. Our results provide a molecular basis for early alterations in epithelial architecture during obesity-mediated cancer initiation.
journal_name
Oncogenejournal_title
Oncogeneauthors
Tenvooren I,Jenks MZ,Rashid H,Cook KL,Muhlemann JK,Sistrunk C,Holmes J,Wang K,Bonin K,Hodges K,Lo HW,Shaikh A,Camarillo IG,Lelièvre SA,Seewaldt V,Vidi PAdoi
10.1038/s41388-019-0687-8subject
Has Abstractpub_date
2019-05-01 00:00:00pages
3855-3870issue
20eissn
0950-9232issn
1476-5594pii
10.1038/s41388-019-0687-8journal_volume
38pub_type
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