Expression of scatter factor and c‐ met receptor in benign and malignant breast tissue

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Abstract
Scatter factor (SF), also known as hepatocyte growth factor, is an angiogenic cytokine that stimulates epithelial cell motility and invasion. Its receptor is a transmembrane tyrosine kinase encoded by the c-met protooncogene. Several prior experimental and clinical studies have suggested that SF might play a role in the development and progression of breast carcinoma. To investigate the possible involvement of SF and c-met in the evolution of breast carcinoma, the authors studied their expression in sections of human breast tissue. A variety of paraffin embedded tissue specimens (of normal breast tissue tissue, benign hyperplasia, ductal carcinoma-in-situ [DCIS], and invasive ductal carcinoma) from 125 patients were immunoperoxidase-stained using specific antisera against SF and c-met. The staining intensities of epithelial mammary cells were scored semiquantitatively, and the staining scores were analyzed as a function of tissue type. In addition, in situ hybridization to detect SF mRNA was performed for a small number of cancer sections. Specific SF staining was observed in tumor cells, normal cell types (epithelium and vascular smooth muscle), and acellular stroma, whereas c- met staining was observed in tumor cells and normal cell types but not in stroma. Analysis of the staining scores of epithelial mammary cells revealed several patterns: (1) SF and c-met staining scores each increased in the following order: normal breast/benign hyperplasias (lowest) --> DCIS (higher) --> invasive carcinoma (highest); (2) normal-appearing mammary ducts and lobules in invasive cancer sections showed less SF and c-met staining than tumor cells in the same specimens but more staining than normal ducts and lobules in sections of normal breast tissue and benign hyperplasia; (3) within the DCIS and invasive cancer groups, SF and c-met staining scores were correlated; and (4) among 40 consecutive cases of DCIS, higher levels of SF and c-met staining showed a trend toward association with other features suggestive of aggressive tumor biology (comedo histology, high nuclear grade, p53 positivity, and bcl-2 negativity). In situ hybridization analysis revealed that the same cell types that expressed SF protein (including tumor cells) also expressed SF mRNA transcripts. SF and c-met are overexpressed in breast carcinoma as compared with benign breast tissue, and they tend to be coexpressed in cancerous tissue. These findings are consistent with the idea that the SF:c-met ligand:receptor pair may have a role in breast carcinoma progression.