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

Abstract

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.

Proteoglycans in mechanobiology of tissues and organs: Normal functions and mechanopathology

“…Literature is accumulating to support the notion that mechanical stiffness can drive PG synthesis in the breast contributing to MD. 191 A recent clinical study compared quantitative proteomics, collagen analysis, PG content, and mechanical measurements in normal and tumoral breast tissue revealing that stroma in the high-density breast contains more oriented, fibrillar collagen with increased content of the PGs, lumican and biglycan. Biglycan increases cancer stem cell properties, nuclear factor-κB signaling, and metastatic behavior in breast cancer cells.…”

“…Regions of high mammographic density (MD) in the breast are characterized by a 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 can drive PG synthesis in the breast contributing to MD 191 . A recent clinical study compared quantitative proteomics, collagen analysis, PG content, and mechanical measurements in normal and tumoral breast tissue revealing that stroma in the high‐density breast contains more oriented, fibrillar collagen with increased content of the PGs, lumican and biglycan.…”

Cell and Tissue Nanomechanics: From Early Development to Carcinogenesis

“…The cytoskeleton plays an important role in mechanosignaling, which modifies cell metabolism, migration, and proliferation. Due to the active participation of the cytoskeleton in cell mechanosignaling processes, it has a direct influence on the regulation of gene expression by influencing nuclear lamins [ 17 , 18 , 19 ]. Cell and cytoskeletal nanomechanics contribute towards not only normal cell growth, but also to cell malignization and tumor growth.…”

Evolution and Self-renewal of the Journal of Mammary Gland Biology and Neoplasia

“…In this issue, we present new research on changes in immune cell types in aging breast [ 16 ], interaction of BRCA1-mutated breast cancer cells with adipose-derived stromal cells [ 17 ], and sensitivity of the mammary glands to dietary fatty acids exposure in utero and postnatally [ 18 ]. Reviews summarize current knowledge on the role of NOTCH signaling in mammary gland development and breast cancer [ 19 ], discuss safety of estetrol-based formulations of contraceptives and menopause hormone therapy for breast health [ 20 ], and provide an appraisal of the relationship between mechanical environment of breast tissue and breast cancer risk with the focus on proteoglycans [ 21 ]. We hope that the Journal of Mammary Gland Biology and Neoplasia will continue to serve its role as the critical platform for disseminating the latest experimental results, for sharing technical approaches and methods, and for the review and discussion of new findings and even provocative ideas in the area of mammary gland development, lactation, and disease.…”