1. Aged Breast Extracellular Matrix Drives Mammary Epithelial Cells to an Invasive and Cancer‐Like Phenotype
- Author
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Gokhan Bahcecioglu, Erin N. Howe, Ian H. Guldner, Xiaoshan S. Yue, M. S. Stack, Siyuan Zhang, Harikrishna Nakshatri, and Pinar Zorlutuna
- Subjects
extracellular matrix ,Science ,General Chemical Engineering ,medicine.medical_treatment ,Cell ,General Physics and Astronomy ,Medicine (miscellaneous) ,Motility ,Breast Neoplasms ,Lysyl oxidase ,Biology ,Biochemistry, Genetics and Molecular Biology (miscellaneous) ,Cell membrane ,Extracellular matrix ,Mice ,breast cancer ,Downregulation and upregulation ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Neoplasm Invasiveness ,General Materials Science ,Breast ,Epithelial–mesenchymal transition ,Research Articles ,Gene knockdown ,epithelial‐mesenchymal transition ,aging ,General Engineering ,Cancer ,medicine.disease ,Mice, Inbred C57BL ,Disease Models, Animal ,Phenotype ,medicine.anatomical_structure ,Cytokine ,Cancer research ,Female ,lysyl oxidase ,Research Article - Abstract
Age is a major risk factor for cancer. While the importance of age related genetic alterations in cells on cancer progression is well documented, the effect of aging extracellular matrix (ECM) has been overlooked. This study shows that the aging breast ECM alone is sufficient to drive normal human mammary epithelial cells (KTB21) to a more invasive and cancer‐like phenotype, while promoting motility and invasiveness in MDA‐MB‐231 cells. Decellularized breast matrix from aged mice leads to loss of E‐cadherin membrane localization in KTB21 cells, increased cell motility and invasion, and increased production of inflammatory cytokines and cancer‐related proteins. The aged matrix upregulates cancer‐related genes in KTB21 cells and enriches a cell subpopulation highly expressing epithelial‐mesenchymal transition‐related genes. Lysyl oxidase knockdown reverts the aged matrix‐induced changes to the young levels; it relocalizes E‐cadherin to cell membrane, and reduces cell motility, invasion, and cytokine production. These results show for the first time that the aging ECM harbors key biochemical, physical, and mechanical cues contributing to invasive and cancer‐like behavior in healthy and cancer mammary cells. Differential response of cells to young and aged ECMs can lead to identification of new targets for cancer treatment and prevention., Aging leads to reduced collagen XV and V, and increased stiffness, cytokine content, collagen and fiber thickness, and curvature in the breast tissue. The aged extracellular matrix, without the cellular components, predisposes the normal and cancer cells to a more invasive phenotype, by changing their gene expression profile. Lysyl oxidase knockdown reverses all the effects.
- Published
- 2021
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