Aged Breast Extracellular Matrix Drives Mammary Epithelial Cells to an Invasive and Cancer‐Like Phenotype

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.

Age alters the oncogenic trajectory toward luminal mammary tumors that activate unfolded proteins responses

“…Third, we performed staining using a peptide that selectively binds to denatured collagen and found that this peptide binds strongly to ducts of aged mammary glands but not young mammary glands (Figure 1m ). These results are in strong agreement with the recent proteomic analysis of young and aged mammary glands, which revealed a significant decrease and alteration in the collagen during aging (Bahcecioglu et al, 2021 ). Therefore, we view these findings as an internal validation of our RNAseq analysis.…”

Recent Advances in the Aging Microenvironment of Breast Cancer

“…The most abundant matrix protein in the extracellular matrix is collagen ( Figure 1 a), which regulates and stabilizes the structural properties of the extracellular matrix [ 17 ]. Aging results in thinner and curvier collagen fibers, forming a denser collagen mesh ( Figure 1 b), resulting in increased breast extracellular matrix stiffness [ 18 ]. A study undertaking a biophysical and biochemical assessment of stromal-epithelial interactions showed that stiffening is associated with breast cancer invasion and aggression.…”

“…Normal mammary epithelial cells (KTB21) were stained with the stroma to detect E-cadherin (E-CAD), and it was interesting to find that E-CAD was localized to the cell membrane in the young matrix ( Figure 1 a), while little membrane localization was observed in the aged matrix ( Figure 1 b) [ 18 ]. E-cadherin, which is derived from epithelial tissues, is a membrane protein that mediates cell-cell adhesion and epithelial tissue homeostasis [ 20 ].…”

“…E-cadherin, which is derived from epithelial tissues, is a membrane protein that mediates cell-cell adhesion and epithelial tissue homeostasis [ 20 ]. MDA-MB-231 breast cancer cells in an aged matrix showed greater motility and invasiveness than those in a young matrix [ 18 ]. E-cadherin is a known tumor suppressor, but Padmanaban et al found that although the loss of E-cadherin increases the invasion of cancer cells, it also reduces the proliferation and survival of cancer cells, thus limiting the distant metastasis of cancer cells.…”

Mechanisms of Cell Adhesion Molecules in Endocrine-Related Cancers: A Concise Outlook

“…N-cadherin-dependent cell-to-cell adhesion is required for migration mediated by bone marrow-derived MSCs towards MDA-MB-231 breast cancer cells via canonical TGF-β signaling ( 106 ). A previous study reported that aging breast ECM alone was sufficient to drive normal human mammary epithelial cells (KTB21) to an invasive and cancer-like phenotype that led to a loss of CDH1 in vivo ( 107 ). CDH1 facilitates metastasis in phenotypically sorted subpopulations of breast cancer cells, enabling clustering of circulating tumor cells ( 108 ).…”