Primary tumour expression of the cysteine cathepsin inhibitor Stefin A inhibits distant metastasis in breast cáncer

BELINDA S. PARKER; DANIEL R. CIOCCA; BRADLEY N. BIDWELL; FRANCISCO E. GAGO; MARIEL A. FANELLI; JOSHY GEORGE; JOHN L. SLAVIN; ANDREAS MÖLLER; ROHAN STEEL; NORMAND POULIOT; BEDRICH L. ECKHARDT; MICHAEL A. HENDERSON; ROBIN L. ANDERSON

JOURNAL OF PATHOLOGY

JOHN WILEY & SONS LTD

Año: 2008 vol. 214 p. 337 - 346

0022-3417

Using the clinically relevant 4T1-derived syngeneic murine model of spontaneous mammary metastasis to bone, we have identified the cysteine cathepsin inhibitor Stefin A as a gene differentially expressed in primary and metastatic mammary tumours. In primary tumours, Stefin A expression inversely correlated with metastatic potential in 4T1-derived lines and was not detected in tumour cells in culture, indicating induction only within the tumour microenvironment. Enforced expression of Stefin A in the highly metastatic 4T1.2 cell line significantly reduced spontaneous bone metastasis, following orthotopic injection into the mammary gland. Consistent with the mouse data, Stefin A expression correlated with disease-free survival (absence of distant metastasis) in a cohort of 142 primary tumours from breast cancer patients. This was most significant for patients with invasive ductal carcinoma expressing Stefin A, who were less likely to develop distant metastases (log rank test p=0.0075). In a multivariate disease free survival analysis (Cox proportional hazards model), Stefin A expression remained a significant independent prognostic factor in patients with invasive ductal carcinoma (p=0.0014) along with grade and PR status. In human lung and bone metastases, we detected irregular Stefin A staining patterns, with expression often localizing to micrometastases (<0.2mm) in direct contact with the stroma. We propose that Stefin A, as a cysteine cathepsin inhibitor, may be a marker of increased cathepsin activity in metastases. The cathepsin inhibitor was detected co-expressed with cathepsin B in lung and bone metastases, both in the murine model and in human tissues, using immunohistology. We conclude that Stefin A expression reduces distant metastasis in breast cancer, and propose that this may be due to the inhibition of cysteine cathepsins such as cathepsin B. In human lung and bone metastases, we detected irregular Stefin A staining patterns, with expression often localizing to micrometastases (<0.2mm) in direct contact with the stroma. We propose that Stefin A, as a cysteine cathepsin inhibitor, may be a marker of increased cathepsin activity in metastases. The cathepsin inhibitor was detected co-expressed with cathepsin B in lung and bone metastases, both in the murine model and in human tissues, using immunohistology. We conclude that Stefin A expression reduces distant metastasis in breast cancer, and propose that this may be due to the inhibition of cysteine cathepsins such as cathepsin B. invasive ductal carcinoma (p=0.0014) along with grade and PR status. In human lung and bone metastases, we detected irregular Stefin A staining patterns, with expression often localizing to micrometastases (<0.2mm) in direct contact with the stroma. We propose that Stefin A, as a cysteine cathepsin inhibitor, may be a marker of increased cathepsin activity in metastases. The cathepsin inhibitor was detected co-expressed with cathepsin B in lung and bone metastases, both in the murine model and in human tissues, using immunohistology. We conclude that Stefin A expression reduces distant metastasis in breast cancer, and propose that this may be due to the inhibition of cysteine cathepsins such as cathepsin B. In human lung and bone metastases, we detected irregular Stefin A staining patterns, with expression often localizing to micrometastases (<0.2mm) in direct contact with the stroma. We propose that Stefin A, as a cysteine cathepsin inhibitor, may be a marker of increased cathepsin activity in metastases. The cathepsin inhibitor was detected co-expressed with cathepsin B in lung and bone metastases, both in the murine model and in human tissues, using immunohistology. We conclude that Stefin A expression reduces distant metastasis in breast cancer, and propose that this may be due to the inhibition of cysteine cathepsins such as cathepsin B. Stefin A expression remained a significant independent prognostic factor in patients with invasive ductal carcinoma (p=0.0014) along with grade and PR status. In human lung and bone metastases, we detected irregular Stefin A staining patterns, with expression often localizing to micrometastases (<0.2mm) in direct contact with the stroma. We propose that Stefin A, as a cysteine cathepsin inhibitor, may be a marker of increased cathepsin activity in metastases. The cathepsin inhibitor was detected co-expressed with cathepsin B in lung and bone metastases, both in the murine model and in human tissues, using immunohistology. We conclude that Stefin A expression reduces distant metastasis in breast cancer, and propose that this may be due to the inhibition of cysteine cathepsins such as cathepsin B. In human lung and bone metastases, we detected irregular Stefin A staining patterns, with expression often localizing to micrometastases (<0.2mm) in direct contact with the stroma. We propose that Stefin A, as a cysteine cathepsin inhibitor, may be a marker of increased cathepsin activity in metastases. The cathepsin inhibitor was detected co-expressed with cathepsin B in lung and bone metastases, both in the murine model and in human tissues, using immunohistology. We conclude that Stefin A expression reduces distant metastasis in breast cancer, and propose that this may be due to the inhibition of cysteine cathepsins such as cathepsin B. invasive ductal carcinoma (p=0.0014) along with grade and PR status. In human lung and bone metastases, we detected irregular Stefin A staining patterns, with expression often localizing to micrometastases (<0.2mm) in direct contact with the stroma. We propose that Stefin A, as a cysteine cathepsin inhibitor, may be a marker of increased cathepsin activity in metastases. The cathepsin inhibitor was detected co-expressed with cathepsin B in lung and bone metastases, both in the murine model and in human tissues, using immunohistology. We conclude that Stefin A expression reduces distant metastasis in breast cancer, and propose that this may be due to the inhibition of cysteine cathepsins such as cathepsin B. In human lung and bone metastases, we detected irregular Stefin A staining patterns, with expression often localizing to micrometastases (<0.2mm) in direct contact with the stroma. We propose that Stefin A, as a cysteine cathepsin inhibitor, may be a marker of increased cathepsin activity in metastases. The cathepsin inhibitor was detected co-expressed with cathepsin B in lung and bone metastases, both in the murine model and in human tissues, using immunohistology. We conclude that Stefin A expression reduces distant metastasis in breast cancer, and propose that this may be due to the inhibition of cysteine cathepsins such as cathepsin B. breast cancer patients. This was most significant for patients with invasive ductal carcinoma expressing Stefin A, who were less likely to develop distant metastases (log rank test p=0.0075). In a multivariate disease free survival analysis (Cox proportional hazards model), Stefin A expression remained a significant independent prognostic factor in patients with invasive ductal carcinoma (p=0.0014) along with grade and PR status. In human lung and bone metastases, we detected irregular Stefin A staining patterns, with expression often localizing to micrometastases (<0.2mm) in direct contact with the stroma. We propose that Stefin A, as a cysteine cathepsin inhibitor, may be a marker of increased cathepsin activity in metastases. The cathepsin inhibitor was detected co-expressed with cathepsin B in lung and bone metastases, both in the murine model and in human tissues, using immunohistology. We conclude that Stefin A expression reduces distant metastasis in breast cancer, and propose that this may be due to the inhibition of cysteine cathepsins such as cathepsin B. In human lung and bone metastases, we detected irregular Stefin A staining patterns, with expression often localizing to micrometastases (<0.2mm) in direct contact with the stroma. We propose that Stefin A, as a cysteine cathepsin inhibitor, may be a marker of increased cathepsin activity in metastases. The cathepsin inhibitor was detected co-expressed with cathepsin B in lung and bone metastases, both in the murine model and in human tissues, using immunohistology. We conclude that Stefin A expression reduces distant metastasis in breast cancer, and propose that this may be due to the inhibition of cysteine cathepsins such as cathepsin B. invasive ductal carcinoma (p=0.0014) along with grade and PR status. In human lung and bone metastases, we detected irregular Stefin A staining patterns, with expression often localizing to micrometastases (<0.2mm) in direct contact with the stroma. We propose that Stefin A, as a cysteine cathepsin inhibitor, may be a marker of increased cathepsin activity in metastases. The cathepsin inhibitor was detected co-expressed with cathepsin B in lung and bone metastases, both in the murine model and in human tissues, using immunohistology. We conclude that Stefin A expression reduces distant metastasis in breast cancer, and propose that this may be due to the inhibition of cysteine cathepsins such as cathepsin B. In human lung and bone metastases, we detected irregular Stefin A staining patterns, with expression often localizing to micrometastases (<0.2mm) in direct contact with the stroma. We propose that Stefin A, as a cysteine cathepsin inhibitor, may be a marker of increased cathepsin activity in metastases. The cathepsin inhibitor was detected co-expressed with cathepsin B in lung and bone metastases, both in the murine model and in human tissues, using immunohistology. We conclude that Stefin A expression reduces distant metastasis in breast cancer, and propose that this may be due to the inhibition of cysteine cathepsins such as cathepsin B. Stefin A expression remained a significant independent prognostic factor in patients with invasive ductal carcinoma (p=0.0014) along with grade and PR status. In human lung and bone metastases, we detected irregular Stefin A staining patterns, with expression often localizing to micrometastases (<0.2mm) in direct contact with the stroma. We propose that Stefin A, as a cysteine cathepsin inhibitor, may be a marker of increased cathepsin activity in metastases. The cathepsin inhibitor was detected co-expressed with cathepsin B in lung and bone metastases, both in the murine model and in human tissues, using immunohistology. We conclude that Stefin A expression reduces distant metastasis in breast cancer, and propose that this may be due to the inhibition of cysteine cathepsins such as cathepsin B. In human lung and bone metastases, we detected irregular Stefin A staining patterns, with expression often localizing to micrometastases (<0.2mm) in direct contact with the stroma. We propose that Stefin A, as a cysteine cathepsin inhibitor, may be a marker of increased cathepsin activity in metastases. The cathepsin inhibitor was detected co-expressed with cathepsin B in lung and bone metastases, both in the murine model and in human tissues, using immunohistology. We conclude that Stefin A expression reduces distant metastasis in breast cancer, and propose that this may be due to the inhibition of cysteine cathepsins such as cathepsin B. invasive ductal carcinoma (p=0.0014) along with grade and PR status. In human lung and bone metastases, we detected irregular Stefin A staining patterns, with expression often localizing to micrometastases (<0.2mm) in direct contact with the stroma. We propose that Stefin A, as a cysteine cathepsin inhibitor, may be a marker of increased cathepsin activity in metastases. The cathepsin inhibitor was detected co-expressed with cathepsin B in lung and bone metastases, both in the murine model and in human tissues, using immunohistology. We conclude that Stefin A expression reduces distant metastasis in breast cancer, and propose that this may be due to the inhibition of cysteine cathepsins such as cathepsin B. In human lung and bone metastases, we detected irregular Stefin A staining patterns, with expression often localizing to micrometastases (<0.2mm) in direct contact with the stroma. We propose that Stefin A, as a cysteine cathepsin inhibitor, may be a marker of increased cathepsin activity in metastases. The cathepsin inhibitor was detected co-expressed with cathepsin B in lung and bone metastases, both in the murine model and in human tissues, using immunohistology. We conclude that Stefin A expression reduces distant metastasis in breast cancer, and propose that this may be due to the inhibition of cysteine cathepsins such as cathepsin B. metastasis to bone, we have identified the cysteine cathepsin inhibitor Stefin A as a gene differentially expressed in primary and metastatic mammary tumours. In primary tumours, Stefin A expression inversely correlated with metastatic potential in 4T1-derived lines and was not detected in tumour cells in culture, indicating induction only within the tumour microenvironment. Enforced expression of Stefin A in the highly metastatic 4T1.2 cell line significantly reduced spontaneous bone metastasis, following orthotopic injection into the mammary gland. Consistent with the mouse data, Stefin A expression correlated with disease-free survival (absence of distant metastasis) in a cohort of 142 primary tumours from breast cancer patients. This was most significant for patients with invasive ductal carcinoma expressing Stefin A, who were less likely to develop distant metastases (log rank test p=0.0075). In a multivariate disease free survival analysis (Cox proportional hazards model), Stefin A expression remained a significant independent prognostic factor in patients with invasive ductal carcinoma (p=0.0014) along with grade and PR status. In human lung and bone metastases, we detected irregular Stefin A staining patterns, with expression often localizing to micrometastases (<0.2mm) in direct contact with the stroma. We propose that Stefin A, as a cysteine cathepsin inhibitor, may be a marker of increased cathepsin activity in metastases. The cathepsin inhibitor was detected co-expressed with cathepsin B in lung and bone metastases, both in the murine model and in human tissues, using immunohistology. We conclude that Stefin A expression reduces distant metastasis in breast cancer, and propose that this may be due to the inhibition of cysteine cathepsins such as cathepsin B. In human lung and bone metastases, we detected irregular Stefin A staining patterns, with expression often localizing to micrometastases (<0.2mm) in direct contact with the stroma. We propose that Stefin A, as a cysteine cathepsin inhibitor, may be a marker of increased cathepsin activity in metastases. The cathepsin inhibitor was detected co-expressed with cathepsin B in lung and bone metastases, both in the murine model and in human tissues, using immunohistology. We conclude that Stefin A expression reduces distant metastasis in breast cancer, and propose that this may be due to the inhibition of cysteine cathepsins such as cathepsin B. invasive ductal carcinoma (p=0.0014) along with grade and PR status. In human lung and bone metastases, we detected irregular Stefin A staining patterns, with expression often localizing to micrometastases (<0.2mm) in direct contact with the stroma. We propose that Stefin A, as a cysteine cathepsin inhibitor, may be a marker of increased cathepsin activity in metastases. The cathepsin inhibitor was detected co-expressed with cathepsin B in lung and bone metastases, both in the murine model and in human tissues, using immunohistology. We conclude that Stefin A expression reduces distant metastasis in breast cancer, and propose that this may be due to the inhibition of cysteine cathepsins such as cathepsin B. In human lung and bone metastases, we detected irregular Stefin A staining patterns, with expression often localizing to micrometastases (<0.2mm) in direct contact with the stroma. We propose that Stefin A, as a cysteine cathepsin inhibitor, may be a marker of increased cathepsin activity in metastases. The cathepsin inhibitor was detected co-expressed with cathepsin B in lung and bone metastases, both in the murine model and in human tissues, using immunohistology. We conclude that Stefin A expression reduces distant metastasis in breast cancer, and propose that this may be due to the inhibition of cysteine cathepsins such as cathepsin B. Stefin A expression remained a significant independent prognostic factor in patients with invasive ductal carcinoma (p=0.0014) along with grade and PR status. In human lung and bone metastases, we detected irregular Stefin A staining patterns, with expression often localizing to micrometastases (<0.2mm) in direct contact with the stroma. We propose that Stefin A, as a cysteine cathepsin inhibitor, may be a marker of increased cathepsin activity in metastases. The cathepsin inhibitor was detected co-expressed with cathepsin B in lung and bone metastases, both in the murine model and in human tissues, using immunohistology. We conclude that Stefin A expression reduces distant metastasis in breast cancer, and propose that this may be due to the inhibition of cysteine cathepsins such as cathepsin B. In human lung and bone metastases, we detected irregular Stefin A staining patterns, with expression often localizing to micrometastases (<0.2mm) in direct contact with the stroma. We propose that Stefin A, as a cysteine cathepsin inhibitor, may be a marker of increased cathepsin activity in metastases. The cathepsin inhibitor was detected co-expressed with cathepsin B in lung and bone metastases, both in the murine model and in human tissues, using immunohistology. We conclude that Stefin A expression reduces distant metastasis in breast cancer, and propose that this may be due to the inhibition of cysteine cathepsins such as cathepsin B. invasive ductal carcinoma (p=0.0014) along with grade and PR status. In human lung and bone metastases, we detected irregular Stefin A staining patterns, with expression often localizing to micrometastases (<0.2mm) in direct contact with the stroma. We propose that Stefin A, as a cysteine cathepsin inhibitor, may be a marker of increased cathepsin activity in metastases. The cathepsin inhibitor was detected co-expressed with cathepsin B in lung and bone metastases, both in the murine model and in human tissues, using immunohistology. We conclude that Stefin A expression reduces distant metastasis in breast cancer, and propose that this may be due to the inhibition of cysteine cathepsins such as cathepsin B. In human lung and bone metastases, we detected irregular Stefin A staining patterns, with expression often localizing to micrometastases (<0.2mm) in direct contact with the stroma. We propose that Stefin A, as a cysteine cathepsin inhibitor, may be a marker of increased cathepsin activity in metastases. The cathepsin inhibitor was detected co-expressed with cathepsin B in lung and bone metastases, both in the murine model and in human tissues, using immunohistology. We conclude that Stefin A expression reduces distant metastasis in breast cancer, and propose that this may be due to the inhibition of cysteine cathepsins such as cathepsin B. breast cancer patients. This was most significant for patients with invasive ductal carcinoma expressing Stefin A, who were less likely to develop distant metastases (log rank test p=0.0075). In a multivariate disease free survival analysis (Cox proportional hazards model), Stefin A expression remained a significant independent prognostic factor in patients with invasive ductal carcinoma (p=0.0014) along with grade and PR status. In human lung and bone metastases, we detected irregular Stefin A staining patterns, with expression often localizing to micrometastases (<0.2mm) in direct contact with the stroma. We propose that Stefin A, as a cysteine cathepsin inhibitor, may be a marker of increased cathepsin activity in metastases. The cathepsin inhibitor was detected co-expressed with cathepsin B in lung and bone metastases, both in the murine model and in human tissues, using immunohistology. We conclude that Stefin A expression reduces distant metastasis in breast cancer, and propose that this may be due to the inhibition of cysteine cathepsins such as cathepsin B. In human lung and bone metastases, we detected irregular Stefin A staining patterns, with expression often localizing to micrometastases (<0.2mm) in direct contact with the stroma. We propose that Stefin A, as a cysteine cathepsin inhibitor, may be a marker of increased cathepsin activity in metastases. The cathepsin inhibitor was detected co-expressed with cathepsin B in lung and bone metastases, both in the murine model and in human tissues, using immunohistology. We conclude that Stefin A expression reduces distant metastasis in breast cancer, and propose that this may be due to the inhibition of cysteine cathepsins such as cathepsin B. invasive ductal carcinoma (p=0.0014) along with grade and PR status. In human lung and bone metastases, we detected irregular Stefin A staining patterns, with expression often localizing to micrometastases (<0.2mm) in direct contact with the stroma. We propose that Stefin A, as a cysteine cathepsin inhibitor, may be a marker of increased cathepsin activity in metastases. The cathepsin inhibitor was detected co-expressed with cathepsin B in lung and bone metastases, both in the murine model and in human tissues, using immunohistology. We conclude that Stefin A expression reduces distant metastasis in breast cancer, and propose that this may be due to the inhibition of cysteine cathepsins such as cathepsin B. In human lung and bone metastases, we detected irregular Stefin A staining patterns, with expression often localizing to micrometastases (<0.2mm) in direct contact with the stroma. We propose that Stefin A, as a cysteine cathepsin inhibitor, may be a marker of increased cathepsin activity in metastases. The cathepsin inhibitor was detected co-expressed with cathepsin B in lung and bone metastases, both in the murine model and in human tissues, using immunohistology. We conclude that Stefin A expression reduces distant metastasis in breast cancer, and propose that this may be due to the inhibition of cysteine cathepsins such as cathepsin B. Stefin A expression remained a significant independent prognostic factor in patients with invasive ductal carcinoma (p=0.0014) along with grade and PR status. In human lung and bone metastases, we detected irregular Stefin A staining patterns, with expression often localizing to micrometastases (<0.2mm) in direct contact with the stroma. We propose that Stefin A, as a cysteine cathepsin inhibitor, may be a marker of increased cathepsin activity in metastases. The cathepsin inhibitor was detected co-expressed with cathepsin B in lung and bone metastases, both in the murine model and in human tissues, using immunohistology. We conclude that Stefin A expression reduces distant metastasis in breast cancer, and propose that this may be due to the inhibition of cysteine cathepsins such as cathepsin B. In human lung and bone metastases, we detected irregular Stefin A staining patterns, with expression often localizing to micrometastases (<0.2mm) in direct contact with the stroma. We propose that Stefin A, as a cysteine cathepsin inhibitor, may be a marker of increased cathepsin activity in metastases. The cathepsin inhibitor was detected co-expressed with cathepsin B in lung and bone metastases, both in the murine model and in human tissues, using immunohistology. We conclude that Stefin A expression reduces distant metastasis in breast cancer, and propose that this may be due to the inhibition of cysteine cathepsins such as cathepsin B. invasive ductal carcinoma (p=0.0014) along with grade and PR status. In human lung and bone metastases, we detected irregular Stefin A staining patterns, with expression often localizing to micrometastases (<0.2mm) in direct contact with the stroma. We propose that Stefin A, as a cysteine cathepsin inhibitor, may be a marker of increased cathepsin activity in metastases. The cathepsin inhibitor was detected co-expressed with cathepsin B in lung and bone metastases, both in the murine model and in human tissues, using immunohistology. We conclude that Stefin A expression reduces distant metastasis in breast cancer, and propose that this may be due to the inhibition of cysteine cathepsins such as cathepsin B. In human lung and bone metastases, we detected irregular Stefin A staining patterns, with expression often localizing to micrometastases (<0.2mm) in direct contact with the stroma. We propose that Stefin A, as a cysteine cathepsin inhibitor, may be a marker of increased cathepsin activity in metastases. The cathepsin inhibitor was detected co-expressed with cathepsin B in lung and bone metastases, both in the murine model and in human tissues, using immunohistology. We conclude that Stefin A expression reduces distant metastasis in breast cancer, and propose that this may be due to the inhibition of cysteine cathepsins such as cathepsin B. the clinically relevant 4T1-derived syngeneic murine model of spontaneous mammary metastasis to bone, we have identified the cysteine cathepsin inhibitor Stefin A as a gene differentially expressed in primary and metastatic mammary tumours. In primary tumours, Stefin A expression inversely correlated with metastatic potential in 4T1-derived lines and was not detected in tumour cells in culture, indicating induction only within the tumour microenvironment. Enforced expression of Stefin A in the highly metastatic 4T1.2 cell line significantly reduced spontaneous bone metastasis, following orthotopic injection into the mammary gland. Consistent with the mouse data, Stefin A expression correlated with disease-free survival (absence of distant metastasis) in a cohort of 142 primary tumours from breast cancer patients. This was most significant for patients with invasive ductal carcinoma expressing Stefin A, who were less likely to develop distant metastases (log rank test p=0.0075). In a multivariate disease free survival analysis (Cox proportional hazards model), Stefin A expression remained a significant independent prognostic factor in patients with invasive ductal carcinoma (p=0.0014) along with grade and PR status. In human lung and bone metastases, we detected irregular Stefin A staining patterns, with expression often localizing to micrometastases (<0.2mm) in direct contact with the stroma. We propose that Stefin A, as a cysteine cathepsin inhibitor, may be a marker of increased cathepsin activity in metastases. The cathepsin inhibitor was detected co-expressed with cathepsin B in lung and bone metastases, both in the murine model and in human tissues, using immunohistology. We conclude that Stefin A expression reduces distant metastasis in breast cancer, and propose that this may be due to the inhibition of cysteine cathepsins such as cathepsin B. In human lung and bone metastases, we detected irregular Stefin A staining patterns, with expression often localizing to micrometastases (<0.2mm) in direct contact with the stroma. We propose that Stefin A, as a cysteine cathepsin inhibitor, may be a marker of increased cathepsin activity in metastases. The cathepsin inhibitor was detected co-expressed with cathepsin B in lung and bone metastases, both in the murine model and in human tissues, using immunohistology. We conclude that Stefin A expression reduces distant metastasis in breast cancer, and propose that this may be due to the inhibition of cysteine cathepsins such as cathepsin B. invasive ductal carcinoma (p=0.0014) along with grade and PR status. In human lung and bone metastases, we detected irregular Stefin A staining patterns, with expression often localizing to micrometastases (<0.2mm) in direct contact with the stroma. We propose that Stefin A, as a cysteine cathepsin inhibitor, may be a marker of increased cathepsin activity in metastases. The cathepsin inhibitor was detected co-expressed with cathepsin B in lung and bone metastases, both in the murine model and in human tissues, using immunohistology. We conclude that Stefin A expression reduces distant metastasis in breast cancer, and propose that this may be due to the inhibition of cysteine cathepsins such as cathepsin B. In human lung and bone metastases, we detected irregular Stefin A staining patterns, with expression often localizing to micrometastases (<0.2mm) in direct contact with the stroma. We propose that Stefin A, as a cysteine cathepsin inhibitor, may be a marker of increased cathepsin activity in metastases. The cathepsin inhibitor was detected co-expressed with cathepsin B in lung and bone metastases, both in the murine model and in human tissues, using immunohistology. We conclude that Stefin A expression reduces distant metastasis in breast cancer, and propose that this may be due to the inhibition of cysteine cathepsins such as cathepsin B. Stefin A expression remained a significant independent prognostic factor in patients with invasive ductal carcinoma (p=0.0014) along with grade and PR status. In human lung and bone metastases, we detected irregular Stefin A staining patterns, with expression often localizing to micrometastases (<0.2mm) in direct contact with the stroma. We propose that Stefin A, as a cysteine cathepsin inhibitor, may be a marker of increased cathepsin activity in metastases. The cathepsin inhibitor was detected co-expressed with cathepsin B in lung and bone metastases, both in the murine model and in human tissues, using immunohistology. We conclude that Stefin A expression reduces distant metastasis in breast cancer, and propose that this may be due to the inhibition of cysteine cathepsins such as cathepsin B. In human lung and bone metastases, we detected irregular Stefin A staining patterns, with expression often localizing to micrometastases (<0.2mm) in direct contact with the stroma. We propose that Stefin A, as a cysteine cathepsin inhibitor, may be a marker of increased cathepsin activity in metastases. The cathepsin inhibitor was detected co-expressed with cathepsin B in lung and bone metastases, both in the murine model and in human tissues, using immunohistology. We conclude that Stefin A expression reduces distant metastasis in breast cancer, and propose that this may be due to the inhibition of cysteine cathepsins such as cathepsin B. invasive ductal carcinoma (p=0.0014) along with grade and PR status. In human lung and bone metastases, we detected irregular Stefin A staining patterns, with expression often localizing to micrometastases (<0.2mm) in direct contact with the stroma. We propose that Stefin A, as a cysteine cathepsin inhibitor, may be a marker of increased cathepsin activity in metastases. The cathepsin inhibitor was detected co-expressed with cathepsin B in lung and bone metastases, both in the murine model and in human tissues, using immunohistology. We conclude that Stefin A expression reduces distant metastasis in breast cancer, and propose that this may be due to the inhibition of cysteine cathepsins such as cathepsin B. In human lung and bone metastases, we detected irregular Stefin A staining patterns, with expression often localizing to micrometastases (<0.2mm) in direct contact with the stroma. We propose that Stefin A, as a cysteine cathepsin inhibitor, may be a marker of increased cathepsin activity in metastases. The cathepsin inhibitor was detected co-expressed with cathepsin B in lung and bone metastases, both in the murine model and in human tissues, using immunohistology. We conclude that Stefin A expression reduces distant metastasis in breast cancer, and propose that this may be due to the inhibition of cysteine cathepsins such as cathepsin B. breast cancer patients. This was most significant for patients with invasive ductal carcinoma expressing Stefin A, who were less likely to develop distant metastases (log rank test p=0.0075). In a multivariate disease free survival analysis (Cox proportional hazards model), Stefin A expression remained a significant independent prognostic factor in patients with invasive ductal carcinoma (p=0.0014) along with grade and PR status. In human lung and bone metastases, we detected irregular Stefin A staining patterns, with expression often localizing to micrometastases (<0.2mm) in direct contact with the stroma. We propose that Stefin A, as a cysteine cathepsin inhibitor, may be a marker of increased cathepsin activity in metastases. The cathepsin inhibitor was detected co-expressed with cathepsin B in lung and bone metastases, both in the murine model and in human tissues, using immunohistology. We conclude that Stefin A expression reduces distant metastasis in breast cancer, and propose that this may be due to the inhibition of cysteine cathepsins such as cathepsin B. In human lung and bone metastases, we detected irregular Stefin A staining patterns, with expression often localizing to micrometastases (<0.2mm) in direct contact with the stroma. We propose that Stefin A, as a cysteine cathepsin inhibitor, may be a marker of increased cathepsin activity in metastases. The cathepsin inhibitor was detected co-expressed with cathepsin B in lung and bone metastases, both in the murine model and in human tissues, using immunohistology. We conclude that Stefin A expression reduces distant metastasis in breast cancer, and propose that this may be due to the inhibition of cysteine cathepsins such as cathepsin B. invasive ductal carcinoma (p=0.0014) along with grade and PR status. In human lung and bone metastases, we detected irregular Stefin A staining patterns, with expression often localizing to micrometastases (<0.2mm) in direct contact with the stroma. We propose that Stefin A, as a cysteine cathepsin inhibitor, may be a marker of increased cathepsin activity in metastases. The cathepsin inhibitor was detected co-expressed with cathepsin B in lung and bone metastases, both in the murine model and in human tissues, using immunohistology. We conclude that Stefin A expression reduces distant metastasis in breast cancer, and propose that this may be due to the inhibition of cysteine cathepsins such as cathepsin B. In human lung and bone metastases, we detected irregular Stefin A staining patterns, with expression often localizing to micrometastases (<0.2mm) in direct contact with the stroma. We propose that Stefin A, as a cysteine cathepsin inhibitor, may be a marker of increased cathepsin activity in metastases. The cathepsin inhibitor was detected co-expressed with cathepsin B in lung and bone metastases, both in the murine model and in human tissues, using immunohistology. We conclude that Stefin A expression reduces distant metastasis in breast cancer, and propose that this may be due to the inhibition of cysteine cathepsins such as cathepsin B. Stefin A expression remained a significant independent prognostic factor in patients with invasive ductal carcinoma (p=0.0014) along with grade and PR status. In human lung and bone metastases, we detected irregular Stefin A staining patterns, with expression often localizing to micrometastases (<0.2mm) in direct contact with the stroma. We propose that Stefin A, as a cysteine cathepsin inhibitor, may be a marker of increased cathepsin activity in metastases. The cathepsin inhibitor was detected co-expressed with cathepsin B in lung and bone metastases, both in the murine model and in human tissues, using immunohistology. We conclude that Stefin A expression reduces distant metastasis in breast cancer, and propose that this may be due to the inhibition of cysteine cathepsins such as cathepsin B. In human lung and bone metastases, we detected irregular Stefin A staining patterns, with expression often localizing to micrometastases (<0.2mm) in direct contact with the stroma. We propose that Stefin A, as a cysteine cathepsin inhibitor, may be a marker of increased cathepsin activity in metastases. The cathepsin inhibitor was detected co-expressed with cathepsin B in lung and bone metastases, both in the murine model and in human tissues, using immunohistology. We conclude that Stefin A expression reduces distant metastasis in breast cancer, and propose that this may be due to the inhibition of cysteine cathepsins such as cathepsin B. invasive ductal carcinoma (p=0.0014) along with grade and PR status. In human lung and bone metastases, we detected irregular Stefin A staining patterns, with expression often localizing to micrometastases (<0.2mm) in direct contact with the stroma. We propose that Stefin A, as a cysteine cathepsin inhibitor, may be a marker of increased cathepsin activity in metastases. The cathepsin inhibitor was detected co-expressed with cathepsin B in lung and bone metastases, both in the murine model and in human tissues, using immunohistology. We conclude that Stefin A expression reduces distant metastasis in breast cancer, and propose that this may be due to the inhibition of cysteine cathepsins such as cathepsin B. In human lung and bone metastases, we detected irregular Stefin A staining patterns, with expression often localizing to micrometastases (<0.2mm) in direct contact with the stroma. We propose that Stefin A, as a cysteine cathepsin inhibitor, may be a marker of increased cathepsin activity in metastases. The cathepsin inhibitor was detected co-expressed with cathepsin B in lung and bone metastases, both in the murine model and in human tissues, using immunohistology. We conclude that Stefin A expression reduces distant metastasis in breast cancer, and propose that this may be due to the inhibition of cysteine cathepsins such as cathepsin B. (absence of distant metastasis) in a cohort of 142 primary tumours from breast cancer patients. This was most significant for patients with invasive ductal carcinoma expressing Stefin A, who were less likely to develop distant metastases (log rank test p=0.0075). In a multivariate disease free survival analysis (Cox proportional hazards model), Stefin A expression remained a significant independent prognostic factor in patients with invasive ductal carcinoma (p=0.0014) along with grade and PR status. In human lung and bone metastases, we detected irregular Stefin A staining patterns, with expression often localizing to micrometastases (<0.2mm) in direct contact with the stroma. We propose that Stefin A, as a cysteine cathepsin inhibitor, may be a marker of increased cathepsin activity in metastases. The cathepsin inhibitor was detected co-expressed with cathepsin B in lung and bone metastases, both in the murine model and in human tissues, using immunohistology. We conclude that Stefin A expression reduces distant metastasis in breast cancer, and propose that this may be due to the inhibition of cysteine cathepsins such as cathepsin B. In human lung and bone metastases, we detected irregular Stefin A staining patterns, with expression often localizing to micrometastases (<0.2mm) in direct contact with the stroma. We propose that Stefin A, as a cysteine cathepsin inhibitor, may be a marker of increased cathepsin activity in metastases. The cathepsin inhibitor was detected co-expressed with cathepsin B in lung and bone metastases, both in the murine model and in human tissues, using immunohistology. We conclude that Stefin A expression reduces distant metastasis in breast cancer, and propose that this may be due to the inhibition of cysteine cathepsins such as cathepsin B. invasive ductal carcinoma (p=0.0014) along with grade and PR status. In human lung and bone metastases, we detected irregular Stefin A staining patterns, with expression often localizing to micrometastases (<0.2mm) in direct contact with the stroma. We propose that Stefin A, as a cysteine cathepsin inhibitor, may be a marker of increased cathepsin activity in metastases. The cathepsin inhibitor was detected co-expressed with cathepsin B in lung and bone metastases, both in the murine model and in human tissues, using immunohistology. We conclude that Stefin A expression reduces distant metastasis in breast cancer, and propose that this may be due to the inhibition of cysteine cathepsins such as cathepsin B. In human lung and bone metastases, we detected irregular Stefin A staining patterns, with expression often localizing to micrometastases (<0.2mm) in direct contact with the stroma. We propose that Stefin A, as a cysteine cathepsin inhibitor, may be a marker of increased cathepsin activity in metastases. The cathepsin inhibitor was detected co-expressed with cathepsin B in lung and bone metastases, both in the murine model and in human tissues, using immunohistology. We conclude that Stefin A expression reduces distant metastasis in breast cancer, and propose that this may be due to the inhibition of cysteine cathepsins such as cathepsin B. Stefin A expression remained a significant independent prognostic factor in patients with invasive ductal carcinoma (p=0.0014) along with grade and PR status. In human lung and bone metastases, we detected irregular Stefin A staining patterns, with expression often localizing to micrometastases (<0.2mm) in direct contact with the stroma. We propose that Stefin A, as a cysteine cathepsin inhibitor, may be a marker of increased cathepsin activity in metastases. The cathepsin inhibitor was detected co-expressed with cathepsin B in lung and bone metastases, both in the murine model and in human tissues, using immunohistology. We conclude that Stefin A expression reduces distant metastasis in breast cancer, and propose that this may be due to the inhibition of cysteine cathepsins such as cathepsin B. In human lung and bone metastases, we detected irregular Stefin A staining patterns, with expression often localizing to micrometastases (<0.2mm) in direct contact with the stroma. We propose that Stefin A, as a cysteine cathepsin inhibitor, may be a marker of increased cathepsin activity in metastases. The cathepsin inhibitor was detected co-expressed with cathepsin B in lung and bone metastases, both in the murine model and in human tissues, using immunohistology. We conclude that Stefin A expression reduces distant metastasis in breast cancer, and propose that this may be due to the inhibition of cysteine cathepsins such as cathepsin B. invasive ductal carcinoma (p=0.0014) along with grade and PR status. In human lung and bone metastases, we detected irregular Stefin A staining patterns, with expression often localizing to micrometastases (<0.2mm) in direct contact with the stroma. We propose that Stefin A, as a cysteine cathepsin inhibitor, may be a marker of increased cathepsin activity in metastases. The cathepsin inhibitor was detected co-expressed with cathepsin B in lung and bone metastases, both in the murine model and in human tissues, using immunohistology. We conclude that Stefin A expression reduces distant metastasis in breast cancer, and propose that this may be due to the inhibition of cysteine cathepsins such as cathepsin B. In human lung and bone metastases, we detected irregular Stefin A staining patterns, with expression often localizing to micrometastases (<0.2mm) in direct contact with the stroma. We propose that Stefin A, as a cysteine cathepsin inhibitor, may be a marker of increased cathepsin activity in metastases. The cathepsin inhibitor was detected co-expressed with cathepsin B in lung and bone metastases, both in the murine model and in human tissues, using immunohistology. We conclude that Stefin A expression reduces distant metastasis in breast cancer, and propose that this may be due to the inhibition of cysteine cathepsins such as cathepsin B. disease free survival analysis (Cox proportional hazards model), Stefin A expression remained a significant independent prognostic factor in patients with invasive ductal carcinoma (p=0.0014) along with grade and PR status. In human lung and bone metastases, we detected irregular Stefin A staining patterns, with expression often localizing to micrometastases (<0.2mm) in direct contact with the stroma. We propose that Stefin A, as a cysteine cathepsin inhibitor, may be a marker of increased cathepsin activity in metastases. The cathepsin inhibitor was detected co-expressed with cathepsin B in lung and bone metastases, both in the murine model and in human tissues, using immunohistology. We conclude that Stefin A expression reduces distant metastasis in breast cancer, and propose that this may be due to the inhibition of cysteine cathepsins such as cathepsin B. In human lung and bone metastases, we detected irregular Stefin A staining patterns, with expression often localizing to micrometastases (<0.2mm) in direct contact with the stroma. We propose that Stefin A, as a cysteine cathepsin inhibitor, may be a marker of increased cathepsin activity in metastases. The cathepsin inhibitor was detected co-expressed with cathepsin B in lung and bone metastases, both in the murine model and in human tissues, using immunohistology. We conclude that Stefin A expression reduces distant metastasis in breast cancer, and propose that this may be due to the inhibition of cysteine cathepsins such as cathepsin B. invasive ductal carcinoma (p=0.0014) along with grade and PR status. In human lung and bone metastases, we detected irregular Stefin A staining patterns, with expression often localizing to micrometastases (<0.2mm) in direct contact with the stroma. We propose that Stefin A, as a cysteine cathepsin inhibitor, may be a marker of increased cathepsin activity in metastases. The cathepsin inhibitor was detected co-expressed with cathepsin B in lung and bone metastases, both in the murine model and in human tissues, using immunohistology. We conclude that Stefin A expression reduces distant metastasis in breast cancer, and propose that this may be due to the inhibition of cysteine cathepsins such as cathepsin B. In human lung and bone metastases, we detected irregular Stefin A staining patterns, with expression often localizing to micrometastases (<0.2mm) in direct contact with the stroma. We propose that Stefin A, as a cysteine cathepsin inhibitor, may be a marker of increased cathepsin activity in metastases. The cathepsin inhibitor was detected co-expressed with cathepsin B in lung and bone metastases, both in the murine model and in human tissues, using immunohistology. We conclude that Stefin A expression reduces distant metastasis in breast cancer, and propose that this may be due to the inhibition of cysteine cathepsins such as cathepsin B. in patients with invasive ductal carcinoma (p=0.0014) along with grade and PR status. In human lung and bone metastases, we detected irregular Stefin A staining patterns, with expression often localizing to micrometastases (<0.2mm) in direct contact with the stroma. We propose that Stefin A, as a cysteine cathepsin inhibitor, may be a marker of increased cathepsin activity in metastases. The cathepsin inhibitor was detected co-expressed with cathepsin B in lung and bone metastases, both in the murine model and in human tissues, using immunohistology. We conclude that Stefin A expression reduces distant metastasis in breast cancer, and propose that this may be due to the inhibition of cysteine cathepsins such as cathepsin B. In human lung and bone metastases, we detected irregular Stefin A staining patterns, with expression often localizing to micrometastases (<0.2mm) in direct contact with the stroma. We propose that Stefin A, as a cysteine cathepsin inhibitor, may be a marker of increased cathepsin activity in metastases. The cathepsin inhibitor was detected co-expressed with cathepsin B in lung and bone metastases, both in the murine model and in human tissues, using immunohistology. We conclude that Stefin A expression reduces distant metastasis in breast cancer, and propose that this may be due to the inhibition of cysteine cathepsins such as cathepsin B. (p=0.0014) along with grade and PR status. In human lung and bone metastases, we detected irregular Stefin A staining patterns, with expression often localizing to micrometastases (<0.2mm) in direct contact with the stroma. We propose that Stefin A, as a cysteine cathepsin inhibitor, may be a marker of increased cathepsin activity in metastases. The cathepsin inhibitor was detected co-expressed with cathepsin B in lung and bone metastases, both in the murine model and in human tissues, using immunohistology. We conclude that Stefin A expression reduces distant metastasis in breast cancer, and propose that this may be due to the inhibition of cysteine cathepsins such as cathepsin B.