The role of TIMP3 in mammary gland morphogenesis, involution, inflammation, and tumourigenesis.
Published: 2006
Language: eng
Number of pages: 242
ISBN-13: 9780494219249
Description: Responsible for producing milk that protects and nourishes the offspring, the mammary gland undergoes cyclical remodeling as dictated by estrous and gestation. The orchestration of mammary gland cell types with local and systemic tissue microenvironment factors can create an epithelial arbor, or differentiate it to secretory units, or even deconstruct the tissue. Ironically, the same remodeling property of the gland renders it susceptible to lesions, including breast cancer.Given the pro-apoptosic and pro-inflammatory roles of TIMP3 loss in involution, its role in mammary tumourigenesis was next investigated. Loss of TIMP3 caused a greater than 90% reduction in tumour burden and metastasis in MMTV-PyMT , an aggressive model of breast cancer. In the non-viral oncogenesis, physiological model, MMTV-Neu, 40% of Timp3 -/- mice were resistant to mammary tumours. Tumours that did emerge in Timp3-/- mice were more malignant. In both models, Timp3 heterozigosity inhibited tumourigenesis. Further, Timp3-null stroma halted the growth of initiated tumours and mammary epithelial cells derived from Timp3-/-  tumours were more sensitive to apoptosis compared to controls. Tumourigenesis attenuation was accompanied by increased infiltration of macrophages, CD4+, and CD8+ T-cells. These studies demonstrate the critical role of TIMP3 during mammary gland physiology and tumourigenesis. Importantly, the loss of one or both Timp3 alleles results in mammary tumour suppression, providing an impetus for exploring TIMP3 as a potential therapeutic target against breast cancer.Extracellular proteolysis mediated by the balanced activity of matrix metalloproteinase (MMP) and tissue inhibitors of metalloproteinases (TIMPs) facilitates mammary gland remodeling. In particular, TIMP3 has the capacity to not only control ECM protein turnover, but also regulate the shedding and bioactivity of ligands and cell surface molecules. The role of TIMP3 in signaling mechanisms governing mammary gland biology were investigated using genetically engineered mice. Timp3-/- primary mammary epithelial cells had increased transcriptional activity of the survival factor, beta-catenin, consistent with an acceleration of epithelial ductal morphogenesis. During post-lactational mammary gland involution, TIMP3 deficiency caused accelerated mammary epithelial apoptosis through a concerted fragmentation of E-cadherin and activation of TNF-dependent apoptosis. Concomitantly, an increased infiltration of macrophages and sustained T-cell presence were observed, which were not mitigated in Timp3-/-/Tnf-/-  mice.
Notes: Source: Dissertation Abstracts International, Volume: 68-01, Section: B, page: 0090.

Thesis (Ph.D.)--University of Toronto, 2006.

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