Abstract
The extracellular protease Adamts1 is a vital enzyme involved in normal development and has been associated with various processes of extracellular matrix (ECM) remodelling including ovulation and pathologies exhibiting disrupted ECM. In the PyMT-MMTV mouse mammary cancer model we have demonstrated reduced tumour growth and pulmonary metastasis incidence in Adamts1–/– mice. Furthermore, benign DCIS lesions of the mammary gland were significantly more common in Adamts1–/– mice. To better understand the mechanisms surrounding Adamts1 mediated progression from DCIS to invasive cancer we next investigated proliferation, apoptosis, blood vessel density and/or extracellular remodelling. Morphometric comparisons were performed using immunohistochemical markers of proliferation (Ki67) and apoptosis (active caspase3) as well as vasculature (CD34), and known Adamts1 proteolytic target, versican in wildtype and Adamts1-/-PyMT tumours. Our analysis revealed that no significant difference in proliferation between the two genotypes, but Adamts1–/– had increased apoptosis compared with Adamts1+/+ tumours. Contrary to previous reports suggesting Adamts1 is antiangiogenic, no significant difference was found in blood vessel density between Adamts1–/– compared with Adamts1+/+ tumours. Interestingly, versican abundance in peritumoural stroma was lower in Adamts1–/– tumours. This latter finding may provide an explanation for the reduced metastasis incidence found after Adamts1gene inactivation, as many previous studies have associated peritumoral versican abundance to metastasic progression. Our findings increase the understanding of mechanisms whereby Adamts1 promotes breast cancer metastasis by showing its role in increasing cell survival, as well as modulating the stromal ECM environment through which it may promote invasion and metastasis. The involvement of Adamts1 in breast cancer progression presents this protease as a potential novel target for reducing metastasis incidence.
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