bcl ‐2 expression in the spectrum of preinvasive breast lesions

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Abstract
The bcl-2 gene encodes for a protein that blocks apoptosis. Although the bcl-2 protein has been identified in some invasive breast cancers, its expression in preinvasive breast lesions has not been well characterized. We studied bcl-2 expression using immunohistochemistry in cases of normal breast tissue (n = 10), ductal hyperplasia (n = 18), atypical ductal hyperplasia (ADH) (n = 10), atypical lobular hyperplasia/lobular carcinoma in situ (lobular neoplasia, LN) (n = 10), and ductal carcinoma in situ (DCIS) (n = 42). We also related bcl-2 expression to p53 expression in these lesions because the p53 gene is altered in many invasive breast cancers and is also involved in the regulation of apoptosis. bcl-2 was consistently expressed in the epithelial cells in all normal breast tissue, ductal hyperplasia, ADH, and LN lesions. In contrast, bcl-2 expression was present in 76% of the DCIS cases and was related to the histologic grade of DCIS. Staining for bcl-2 was observed in 100% of the well differentiated DCIS cases, 90% of intermediately differentiated cases, and 33% of poorly differentiated cases (P < 0.001). No immunoreactivity for the p53 protein was seen in any of the cases of normal breast tissue, ductal hyperplasia, ADH, or LN lesions. However, 24% of the DCIS cases were p53 positive. The bcl-2+/p53- phenotype, as seen in all cases of normal breast tissue, ductal hyperplasia, ADH, and LN was also observed in 67% of the DCIS cases. In contrast, the remaining 33% of DCIS cases showed combinations of bcl-2 and p53 expression that differed from that of normal breast epithelium and the other pathologic lesions studied. Most lesions with altered bcl-2/p53 phenotypes, including all bcl-2-/p53+ cases, represented examples of poorly differentiated DCIS. The bcl-2 protein is consistently expressed in normal breast epithelium, ductal hyperplasia, ADH, and LN. bcl-2 expression is variable in DCIS. Among DCIS cases, bcl-2 is most common in well differentiated and intermediately differentiated lesions. Most DCIS lesions are bcl-2+ and p53-, similar to normal epithelium, benign proliferative lesions, and LN. However, a minority of DCIS lesions show combinations of bcl-2 and p53 expression that differ from normal breast epithelium and from the other pathologic lesions studied. It is possible that such lesions may represent a subset of DCIS in which the regulation of apoptosis is no longer under normal control mechanisms, resulting in enhanced tumor cell survival and tumor growth.