Stiff stroma increases breast cancer risk by inducing the oncogene ZNF217

Northey, Jason J.; Barrett, Alexander S.; Acerbi, Irene; Hayward, Mary-Kate; Talamantes, Stephanie; Dean, Ivory; Mouw, Janna K.; Ponik, Suzanne M.; Lakins, Johnathon N.; Huang, Po-Jui; Wu, Junmin; Shi, Quanming; Samson, Susan L.; Keely, Patricia J.; Mukhtar, Rita A.; Liphardt, Jan; Shepherd, John; Hwang, E. Shelley; Chen, Yunn-Yi; Hansen, Kirk C.; Littlepage, Laurie E.; Weaver, Valerie M.

doi:10.1172/jci129249

Cited by 88 publications

(90 citation statements)

References 94 publications

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“…Stromal cells contribute to ECM and tissue stiffness and, at the same time, a high stiffness matrix has been suggested to be important for maintaining an invasive phenotype 37 , as well as favoring EMT 68 facilitating the transition from epithelial and non-motile phenotype to a mesenchymal and motile (invasive) phenotype providing cellular motility 69 . In the case of breast cancer, it has been shown that denser breast tissue is a risk factor for breast cancer development 70 , 71 . Such increased breast density is a result of increased connective tissue deposition and ECM components, mostly collagen 70 , which is not only increased in deposition but also more oriented, stiffer, and correlated with higher epithelial cell density 71 .…”

Section: Tissue Mechanics On Disease: Ecm Deposition Topographic Reconfiguration Of the Stroma And Cell Contribution To Tissue Stiffnessmentioning

confidence: 99%

“…In the case of breast cancer, it has been shown that denser breast tissue is a risk factor for breast cancer development 70 , 71 . Such increased breast density is a result of increased connective tissue deposition and ECM components, mostly collagen 70 , which is not only increased in deposition but also more oriented, stiffer, and correlated with higher epithelial cell density 71 . Collagen alignment has also been seen to have potential as a prognostic marker for invasive breast carcinoma patients 72 , 73 .…”

Section: Tissue Mechanics On Disease: Ecm Deposition Topographic Reconfiguration Of the Stroma And Cell Contribution To Tissue Stiffnessmentioning

confidence: 99%

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Causal contributors to tissue stiffness and clinical relevance in urology

et al. 2021

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Mechanomedicine is an emerging field focused on characterizing mechanical changes in cells and tissues coupled with a specific disease. Understanding the mechanical cues that drive disease progression, and whether tissue stiffening can precede disease development, is crucial in order to define new mechanical biomarkers to improve and develop diagnostic and prognostic tools. Classically known stromal regulators, such as fibroblasts, and more recently acknowledged factors such as the microbiome and extracellular vesicles, play a crucial role in modifications to the stroma and extracellular matrix (ECM). These modifications ultimately lead to an alteration of the mechanical properties (stiffness) of the tissue, contributing to disease onset and progression. We describe here classic and emerging mediators of ECM remodeling, and discuss state-of-the-art studies characterizing mechanical fingerprints of urological diseases, showing a general trend between increased tissue stiffness and severity of disease. Finally, we point to the clinical potential of tissue stiffness as a diagnostic and prognostic factor in the urological field, as well as a possible target for new innovative drugs.

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Section: Tissue Mechanics On Disease: Ecm Deposition Topographic Reconfiguration Of the Stroma And Cell Contribution To Tissue Stiffnessmentioning

confidence: 99%

Section: Tissue Mechanics On Disease: Ecm Deposition Topographic Reconfiguration Of the Stroma And Cell Contribution To Tissue Stiffnessmentioning

confidence: 99%

Causal contributors to tissue stiffness and clinical relevance in urology

et al. 2021

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“…Indeed, some estimate that HMD may account for up to one third of breast cancers 12 . HMD is associated with increased peri-ductal stromal stiffness and thus altered mechanotransduction 13,14 Given there is now a general understanding that many aspects of cell behaviour are governed by mechanotransduction 27 , we here examined the effects of increased altered ECM stiffness on MECs, using a mechanically-tuneable 3D hydrogel system 13 . By examining global changes in gene expression induced by increased ECM stiffness, we identified significant changes within multiple metabolic pathways.…”

Section: Discussionmentioning

confidence: 99%

“…High mammographic density (HMD) is associated with changes in the composition and organisation of the collagen within the periductal stroma, leading to increased stromal stiffness 13 . Thus, altered mechanosignalling may promote changes within breast cell behaviour that promote tumour initiation 14 .…”

Section: Introductionmentioning

confidence: 99%

Increased microenvironment stiffness leads to altered aldehyde metabolism and DNA damage in mammary epithelial cells through a RhoA-dependent mechanism

Wood

Sun

Jones

et al. 2020

Preprint

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SummaryMicroenvironmental stiffness regulates the behaviour of both normal and cancer cells. In breast tissue, high mammographic density (HMD), which reflects greater organisation and stiffness of the periductal collagen, represents a significant risk factor for cancer. However, the mechanistic link between extracellular matrix (ECM) stiffness and increased risk of breast tumour initiation remains unclear. In particular, how increased ECM stiffness might promote genomic damage, leading to the acquisition of transforming mutations, remains to be determined. Here we determine that ECM stiffness induces changes in mammary epithelial cell (MEC) metabolism that drive genomic damage. Using a 3D-culture model, we demonstrate that genome-wide transcriptional changes in response to increased ECM stiffness impair the ability of MECs to remove reactive aldehyde species, resulting in greater accumulation of DNA damage in a RhoA-dependent manner. Together, our results provide a mechanistic link between increased ECM stiffness and the genomic damage required for breast cancer initiation.

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“…Certainly in idiopathic pulmonary fibrosis, which is associated with the development of lung cancer [212], anti-fibrotic agents are protective [213]. Furthermore, the abundance of fibroblast activation protein (FAP), found to be more abundant in tissues with high MD [45], predicts a poor clinical response in various cancers, and is proving a viable target for inhibition to limit cancer progression [214]. This suggests that inactivating the cell that produces ECM and thus intra-tumoral pressure, the fibroblast, is a useful strategy.…”

Section: Take the Pressure Down: Ways To Reduce The Detrimental Effects Of Force Within Tissuesmentioning

confidence: 99%

Mechanical Pressure Driving Proteoglycan Expression in Mammographic Density: a Self-perpetuating Cycle?

Reye

Huang

Haupt

et al. 2021

J Mammary Gland Biol Neoplasia

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Regions of high mammographic density (MD) in the breast are characterised by a proteoglycan (PG)-rich fibrous stroma, where PGs mediate aligned collagen fibrils to control tissue stiffness and hence the response to mechanical forces. Literature is accumulating to support the notion that mechanical stiffness may drive PG synthesis in the breast contributing to MD. We review emerging patterns in MD and other biological settings, of a positive feedback cycle of force promoting PG synthesis, such as in articular cartilage, due to increased pressure on weight bearing joints. Furthermore, we present evidence to suggest a pro-tumorigenic effect of increased mechanical force on epithelial cells in contexts where PG-mediated, aligned collagen fibrous tissue abounds, with implications for breast cancer development attributable to high MD. Finally, we summarise means through which this positive feedback mechanism of PG synthesis may be intercepted to reduce mechanical force within tissues and thus reduce disease burden.

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Stiff stroma increases breast cancer risk by inducing the oncogene ZNF217

Cited by 88 publications

References 94 publications

Causal contributors to tissue stiffness and clinical relevance in urology

Causal contributors to tissue stiffness and clinical relevance in urology

Increased microenvironment stiffness leads to altered aldehyde metabolism and DNA damage in mammary epithelial cells through a RhoA-dependent mechanism

Mechanical Pressure Driving Proteoglycan Expression in Mammographic Density: a Self-perpetuating Cycle?

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