The global objective of this research is to clarify the relevance of interstitial collagen remodeling in breast tumor progression. Neoplastic progression in the breast is accompanied by a desmoplastic response which is characterized by significant remodeling of interstitial collagen and is associated with a progressive stiffening of the tissue. Progressively transformed mammary epithelial cells (MECs) become sensitized to extracellular matrix (ECM) stiffness, implying that it is the dialogue between a dynamically evolving microenvironment and a progressively aberrant mammary epithelium that is key for neoplastic progression. ECM-degrading matrix metalloproteinases (MMPs) expressed in the stroma cleave interstitial collagen and contribute to the pathogenesis of tumor progression, and elevated MMP expression is predictive of neoplastic progression of human breast lesions. Yet clinical trials with MMP inhibitors failed, suggesting other parameters of ECM remodeling modulate tumor behavior. The lysyl oxidase and lysyl hydroxylase family of enzymes are also expressed in the stroma where they cross-link collagen fibrils to enhance the mechanical integrity of the tissue. These enzymes are also elevated in tumors and contribute to tissue fibrosis. Indeed, the levels of collagen and matrix proteins that enhance ECM stiffness are elevated in women with mammographically dense breasts, who are at higher risk for breast cancer. These data emphasize the importance of collagen cross-linking as well as MMP-degradation to breast cancer progression. Nevertheless, our understanding of the role of collagen cross linking to tumor progression is limited. The goal for this proposal is to dissect, in molecular and cell biological detail, how collagen cross-linking, which stiffens the ECM, contributes to breast cancer progression to a malignant phenotype. Given that tumor progression is mediated through elevated levels/activity of oncogenes and reduced levels/activity of tumor suppressors we suggest that collagen remodeling/stiffening influences tumor progression by modifying the levels/activity of key oncogenes or tumor suppressors. Consistently, we found that ECM cross-linking and stiffness enhance integrin and growth factor receptor (GFR) signaling and regulate levels of the tumor suppressor PTEN. Accordingly, we hypothesize that collagen cross-linking stiffens the tissue to promote breast transformation by enhancing integrin-GFR signaling and reducing the levels of tumor suppressors such as PTEN. The project will take an interdisciplinary approach, using engineering methods to measure and manipulate ECM materials properties and topology in culture and in vivo, together with molecular cell biology methods and genetic mouse models to investigate whether collagen remodeling and cross-linking promote tumor progression by stiffening the breast tissue to enhance integrin and GFR signaling and/or compromising PTEN expression/function. Archived and fresh biopsies of pre-neoplastic breast tissue from women at high and low risk for collagen abundance and structure will establish clinical relevance. We will exploit live cell imaging of organotypic cultures in two- and three-dimensions in natural and synthetic matrices with modified cross-linking, stiffness and topology and will use mice that have been pharmacologically or antibody-modified to have altered collagen structures to interrogate whether collagen cross-linking and stiffness influence MEC motility and invasion by enhancing PI3 kinase signaling to promote chemotaxis and durotaxis. These experiments will give insight into how collagen abundance and cross-linking contribute to the progression of pre-neoplastic lesions to invasive breast cancer. This knowledge will assist in the development of approaches to identify and characterize molecular mechanisms driving breast tumor progression to invasion. The studies will lay the groundwork for future studies aimed at clarifying the role of the tissue ECM in metastasis and treatment response. The work will eventually help to achieve the long-term goal of finding cures for breast cancer and is directly pertinent for other tumor types.

Public Health Relevance

Breast cancer is the second leading cause of cancer deaths in women and is the most common cancer among women. This study addresses an important aspect of women's health, of how collagen, a major component of breast density contributes to risk for breast cancer. The approaches used in this project will elucidate how the structural microenvironment may influence the critical conversion of pre-neoplastic breast epithelium to invasive breast cancer and invasive breast cancer to metastatic breast cancer. From these studies we hope to identify patient populations at higher risk for malignant progression so that these individuals can benefit from improved monitoring and specialized treatment. Our studies also should clarify the origins of nonpalpable versus palpable breast lesions. If we could understand the underlying molecular mechanisms driving mechano-mediated breast neoplastic progression, we will be able to develop better detection, prevention and treatment modalities.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Tumor Microenvironment Study Section (TME)
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Mohla, Suresh
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University of California San Francisco
Schools of Medicine
San Francisco
United States
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Tharp, Kevin M; Weaver, Valerie M (2018) Modeling Tissue Polarity in Context. J Mol Biol 430:3613-3628
Gilbert, Penney M; Weaver, Valerie M (2017) Cellular adaptation to biomechanical stress across length scales in tissue homeostasis and disease. Semin Cell Dev Biol 67:141-152
Miroshnikova, Yekaterina A; Mouw, Janna K; Barnes, J Matthew et al. (2016) Tissue mechanics promote IDH1-dependent HIF1?-tenascin C feedback to regulate glioblastoma aggression. Nat Cell Biol 18:1336-1345
Takai, Ken; Le, Annie; Weaver, Valerie M et al. (2016) Targeting the cancer-associated fibroblasts as a treatment in triple-negative breast cancer. Oncotarget 7:82889-82901
Ou, Guanqing; Thakar, Dhruv; Tung, Jason C et al. (2016) Visualizing mechanical modulation of nanoscale organization of cell-matrix adhesions. Integr Biol (Camb) 8:795-804
Laklai, Hanane; Miroshnikova, Yekaterina A; Pickup, Michael W et al. (2016) Genotype tunes pancreatic ductal adenocarcinoma tissue tension to induce matricellular fibrosis and tumor progression. Nat Med 22:497-505
Kai, FuiBoon; Laklai, Hanane; Weaver, Valerie M (2016) Force Matters: Biomechanical Regulation of Cell Invasion and Migration in Disease. Trends Cell Biol 26:486-497
Kaushik, Shelly; Pickup, Michael W; Weaver, Valerie M (2016) From transformation to metastasis: deconstructing the extracellular matrix in breast cancer. Cancer Metastasis Rev 35:655-667
Tung, Jason C; Barnes, J Matthew; Desai, Shraddha R et al. (2015) Tumor mechanics and metabolic dysfunction. Free Radic Biol Med 79:269-80
Ou, Guanqing; Weaver, Valerie Marie (2015) Tumor-induced solid stress activates ?-catenin signaling to drive malignant behavior in normal, tumor-adjacent cells. Bioessays 37:1293-7

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