Invasion and Proteases

An increase in expression of enzymes capable of degrading basement membranes and extracellular matrix would be expected to occur in the progression to invasive cancer. This has been observed for cathepsin D (Zhao et al., 1993; Schultz et al., 1994), type IV collagenases (Davies et al., 1993; Polette et al., 1993), and stromelysin 3 (Basset etal., 1990;Hahneletal., 1993,1994;Kawamietal., 1993; Wolf etal., 1993). However, altered expression can also be detected in benign breast lesions.

Three forms of cathepsin D with molecular weights of 27 kDa, 31 kDa, and 52 kDa were described in patient sera, and the proportion of the 31-kDa form was found to increase from 1.8% in normal controls to 13% in patients with proliferative breast disease and to 24% in cancer patients (Schultz et al., 1994).

Quantitative in situ hybridization indicated a significant increase in cathepsin D mRNA in breast cancer cells compared to epithelial cells of benign mastopathies, but cathepsin D expression was higher in hyperplastic ductal epithelial cells than in lobules (Zhao et al., 1993). However, lobular carcinomas are more frequentiy positive for cathepsin D expression than are invasive ductal breast carcinomas (Domagala et al., 1993), so the significance of the differential expression in hyperplastic ductular and lobular epithelium is questionable.

Type IV collagenases may also be expressed in benign lesions. One study reported that 2/6 benign lesions and 13/17 invasive breast cancers expressed the 72 kDa, type IV collagenase (Polette et al., 1993), and another reported the detection by in situ hybridization of both 72-kDa and 92-kDa forms in breast cancers, fibroadenomas, and benign breast ducts and acini (Soini et al., 1994).

The epithelium predominantiy expressed the 92-kDa form whereas stromal cells and endothelial cells more strongly expressed the 72-kDa form. The benign lesions were not well described in these studies and interpretation is difficult. Production of a 62-kDa activated foim of the 72-kDa gelatinase was reported to increase in benign breast lesions (9 fibroadenomas and 2 fibrocystic disease cases), and production continued to increase with progression to DCIS and invasive carcinoma (Lee et al., 1996).

Although stromelysin 3 is expressed by the stromal cells in close proximity to epithelial breast lesions, altered expression is probably a response to factors provided by the epithelium (Basset et al., 1993; Patel and Schrey, 1995). Few studies have examined expression of stromelysin in benign lesions, although fibroadenomas were reported to be negative (Hahnel et al., 1994).

Uninvolved breast epithelium from cancer patients was also negative (Hahnel et al., 1993). Expression of stromelysin 3 by stromal cells occurs in most invasive cancers and in some DCIS (Hahnel et al., 1993, 1994; Engel et al., 1994). Levels of stromelysin are significantly higher in invasive cancer than CIS and higher in invasive ductular carcinoma than in invasive lobular carcinoma (Engel et al., 1994). Perhaps stromelysin 3 expression will identify a subset of CIS lesions that progress to invasive carcinoma more rapidly.