PT  - JOURNAL ARTICLE
AU  - Jensen N. Amens
AU  - Gökhan Bahçecioglu
AU  - Kiera Dwyer
AU  - Xiaoshan S. Yue
AU  - M. Sharon Stack
AU  - Tyvette S. Hilliard
AU  - Pinar Zorlutuna
TI  - Maternal obesity driven changes in collagen linearity of breast extracellular matrix induces invasive mammary epithelial cell phenotype
AID  - 10.1101/2022.11.29.518205
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.11.29.518205
4099  - http://biorxiv.org/content/early/2022/12/02/2022.11.29.518205.short
4100  - http://biorxiv.org/content/early/2022/12/02/2022.11.29.518205.full
AB  - Obesity has been linked with numerous health issues as well as an increased risk of breast cancer. Although effects of direct obesity in patient outcomes is widely studied, effects of exposure to obesity-related systemic influences in utero has been overlooked. In this study, we investigated the effect of multigenerational obesity on epithelial cell migration and invasion using decellularized breast tissues explanted from normal female mouse pups from a diet induced multigenerational obesity mouse model. We first studied the effect of multigenerational diet on the mechanical properties, adipocyte size, and collagen structure of these mouse breast tissues, and then, examined the migration and invasion behavior of normal (KTB-21) and cancerous (MDA-MB-231) human mammary epithelial cells on the decellularized matrices from each diet group. Breast tissues of mice whose dams had been fed with high-fat diet exhibited larger adipocytes and thicker and curvier collagen fibers, but only slightly elevated elastic modulus and inflammatory cytokine levels. MDA-MB-231 cancer cell motility and invasion were significantly greater on the decellularized matrices from mice whose dams were fed with high-fat diet. A similar trend was observed with normal KTB-21 cells. Our results showed that the collagen curvature was the dominating factor on this enhanced motility and stretching the matrices to equalize the collagen fiber linearity of the matrices ameliorated the observed increase in cell migration and invasion in the mice that were exposed to a high-fat diet. Previous studies indicated an increase in serum leptin concentration for those children born to an obese mother. We generated extracellular matrices using primary fibroblasts exposed to various concentrations of leptin. This produced curvier ECM and increased breast cancer cell motility for cells seeded on the decellularized ECM generated with increasing leptin concentration. Our study shows that exposure to obesity in utero is influential in determining the extracellular matrix structure, and that the resultant changes in collagen curvature is a critical factor in regulating the migration and invasion of breast cancer cells.Competing Interest StatementThe authors have declared no competing interest.