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

Abstract

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 correlated inversely 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 progesterone receptor (PR) status. In human lung and bone metastases, we detected irregular Stefin A staining patterns, with expression often localizing to micrometastases (<0.2 mm) 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. Using immunohistology, the cathepsin inhibitor was detected co-expressed with cathepsin B in lung and bone metastases in both the murine model and human tissues. 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.

Expression profiling of supraglottic carcinoma: PTEN and thrombospondin 2 are associated with inhibition of lymphatic metastasis

“…Cathepsins have various roles in cancer progression, matrix degradation and cell invasion [5]. Furthermore, they were associated with the progression and metastasis of oral squamous cell carcinoma [6], endometrial carcinoma [7], and breast cancer [8]. The administration of their inhibitors prevents the invasion and metastasis of cancer cells.…”

Expression and clinical significance of cathepsin B and stefin A in laryngeal cancer

“…The cathepsin B content in breast cancer is significantly higher than in adjacent normal mucosa; furthermore, high expression of cathepsin B predicts recurrence and a low 5-year survival rate (8). In addition, overexpression of stefin A was found to suppress the distant metastasis of breast cancer, which may be associated with the suppression of proteases such as cathepsin B (9). In patients with head and neck squamous cell carcinoma, no relationship has been found between cathepsin B expression and survival rate or prognosis, while stefin A was found to be closely associated with survival rate.…”

Microenvironmental Influences on Metastasis Suppressor Expression and Function during a Metastatic Cell’s Journey

“…Alterations in the balance between cathepsin B and stefin A (which is also true for other protease inhibitor interactions, such as matrix metalloproteinases and TIMPs) regulate invasiveness (and metastasis) in a variety of malignant tumors. Stefin A expression correlated with disease-free survival and less distant metastasis in breast cancer patients [103].…”

“…Stefin A Stefin A suppresses metastasis in human esophageal squamous cell carcinoma and murine mammary carcinomas [103,104]. It is an endogenous inhibitor of cathepsin B, a cysteine protease, which promotes invasion [105].…”