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. 1999 Oct;155(4):1253-60.
doi: 10.1016/S0002-9440(10)65227-3.

Immunohistochemical evidence of loss of PTEN expression in primary ductal adenocarcinomas of the breast

A Perren  1 , L P Weng, A H Boag, U Ziebold, K Thakore, P L Dahia, P Komminoth, J A Lees, L M Mulligan, G L Mutter, C Eng
Affiliations

Immunohistochemical evidence of loss of PTEN expression in primary ductal adenocarcinomas of the breast

A Perren et al. Am J Pathol. 1999 Oct.

Abstract

Germline mutations in PTEN, encoding a dual-specificity phosphatase on 10q23.3, cause Cowden syndrome (CS), which is characterized by a high risk of breast and thyroid cancers. Loss of heterozygosity of 10q22-24 markers and somatic PTEN mutations have been found to a greater or lesser extent in a variety of sporadic component and noncomponent cancers of CS. Among several series of sporadic breast carcinomas, the frequency of loss of flanking markers around PTEN is approximately 30 to 40%, and the somatic intragenic PTEN mutation frequency is <5%. In this study, we analyzed PTEN expression in 33 sporadic primary breast carcinoma samples using immunohistochemistry and correlated this to structural studies at the molecular level. Normal mammary tissue had a distinctive pattern of expression: myoepithelial cells uniformly showed strong PTEN expression. The PTEN protein level in mammary epithelial cells was variable. Ductal hyperplasia with and without atypia exhibited higher PTEN protein levels than normal mammary epithelial cells. Among the 33 carcinoma samples, 5 (15%) were immunohistochemically PTEN-negative; 6 (18%) had reduced staining, and the rest were PTEN-positive. In the PTEN-positive tumors as well as in normal epithelium, the protein was localized in the cytoplasm and in the nucleus (or nuclear membrane). Among the immunostain negative group, all had hemizygous PTEN deletion but no structural alteration of the remaining allele. Thus, in these cases, an epigenetic phenomenon such as hypermethylation, -ecreased protein synthesis or increased protein degradation may be involved. In the cases with reduced staining, 5 of 6 had hemizygous PTEN deletion and 1 did not have any structural abnormality. Finally, clinicopathological features were analyzed against PTEN protein expression. Three of the 5 PTEN immunostain-negative carcinomas were also both estrogen and progesterone receptor-negative, whereas only 5 of 22 of the PTEN-positive group were double receptor-negative. The significance of this last observation requires further study.

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Figures

Figure 1.
Figure 1.
Western blot of 7 breast cancer cell lines using the anti-PTEN monoclonal antibody 6H2.1 (left panel) and using the anti-α-tubulin antibody as a control (right panel). MCF-7, T-47D, and MDA-MB-435S have endogenous PTEN. BT-549 and MDA-MB-468 are PTEN-null. ZR-75-1 has monoallelic PTEN deletion and a missense mutation on the remaining allele. MCF-7/PTEN is the MCF-7 line transfected with a wild-type PTEN construct and a tetracycline-inducible promoter after withdrawal of tetracycline and, hence, induced expression of PTEN.
Figure 2.
Figure 2.
A: Ductal hyperplasia (case 58) with increased staining in the epithelial layer (original magnification, ×60). B: Normal breast glands (case 46) with predominantly nuclear staining in the myoepithelial layer (original magnification, ×60). C (case 48) and D (case 43): Ductal carcinoma with strong PTEN staining (++, original magnification, ×30). E: Ductal PTEN-negative carcinoma (arrowhead, case 58) and surrounding normal duct (arrow). Original magnification, ×30. F: Ductal PTEN-negative carcinoma (arrowhead, case 46) with non-neoplastic normal duct (arrow). Original magnification, ×30.
Figure 3.
Figure 3.
Cases with weak staining (arrows in C and F, non-neoplastic duct; arrow in E, blood vessel). A: Ductal carcinoma (case 40) showing no staining (graded −) in the invasive component (top) adjacent to immunostain-positive intraductal component (bottom). B: Case 66. C: Case 59. D: Case 57. E: Case 45. Original magnification, ×30.
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