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

Aurel Perren, Liang Ping Weng, Alexander H. Boag, Ulricke Ziebold, Kosha Thakore, Patricia L Dahia, Paul Komminoth, Jacqueline A. Lees, Lois M. Mulligan, George L. Mutter, Charis Eng

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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, decreased protein synthesis or increased protein degradation may be involved. In the cases with reduced staining, 5 of 6 had hemizygous PTEN deletion and I 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.

Original languageEnglish (US)
Pages (from-to)1253-1260
Number of pages8
JournalAmerican Journal of Pathology
Volume155
Issue number4
StatePublished - Oct 1999
Externally publishedYes

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PTEN Phosphohydrolase
Multiple Hamartoma Syndrome
Adenocarcinoma
Breast
Breast Neoplasms
Epithelial Cells
Dual-Specificity Phosphatases
Staining and Labeling
Carcinoma
Germ-Line Mutation
Loss of Heterozygosity
Nuclear Envelope
Mutation Rate
Progesterone Receptors
Thyroid Neoplasms
Epigenomics
Estrogen Receptors
Proteolysis
Hyperplasia
Neoplasms

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Perren, A., Weng, L. P., Boag, A. H., Ziebold, U., Thakore, K., Dahia, P. L., ... Eng, C. (1999). Immunohistochemical evidence of loss of PTEN expression in primary ductal adenocarcinomas of the breast. American Journal of Pathology, 155(4), 1253-1260.

Immunohistochemical evidence of loss of PTEN expression in primary ductal adenocarcinomas of the breast. / Perren, Aurel; Weng, Liang Ping; Boag, Alexander H.; Ziebold, Ulricke; Thakore, Kosha; Dahia, Patricia L; Komminoth, Paul; Lees, Jacqueline A.; Mulligan, Lois M.; Mutter, George L.; Eng, Charis.

In: American Journal of Pathology, Vol. 155, No. 4, 10.1999, p. 1253-1260.

Research output: Contribution to journalArticle

Perren, A, Weng, LP, Boag, AH, Ziebold, U, Thakore, K, Dahia, PL, Komminoth, P, Lees, JA, Mulligan, LM, Mutter, GL & Eng, C 1999, 'Immunohistochemical evidence of loss of PTEN expression in primary ductal adenocarcinomas of the breast', American Journal of Pathology, vol. 155, no. 4, pp. 1253-1260.
Perren, Aurel ; Weng, Liang Ping ; Boag, Alexander H. ; Ziebold, Ulricke ; Thakore, Kosha ; Dahia, Patricia L ; Komminoth, Paul ; Lees, Jacqueline A. ; Mulligan, Lois M. ; Mutter, George L. ; Eng, Charis. / Immunohistochemical evidence of loss of PTEN expression in primary ductal adenocarcinomas of the breast. In: American Journal of Pathology. 1999 ; Vol. 155, No. 4. pp. 1253-1260.
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title = "Immunohistochemical evidence of loss of PTEN expression in primary ductal adenocarcinomas of the breast",
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, decreased protein synthesis or increased protein degradation may be involved. In the cases with reduced staining, 5 of 6 had hemizygous PTEN deletion and I 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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AU - Perren, Aurel

AU - Weng, Liang Ping

AU - Boag, Alexander H.

AU - Ziebold, Ulricke

AU - Thakore, Kosha

AU - Dahia, Patricia L

AU - Komminoth, Paul

AU - Lees, Jacqueline A.

AU - Mulligan, Lois M.

AU - Mutter, George L.

AU - Eng, Charis

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N2 - 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, decreased protein synthesis or increased protein degradation may be involved. In the cases with reduced staining, 5 of 6 had hemizygous PTEN deletion and I 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.

AB - 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, decreased protein synthesis or increased protein degradation may be involved. In the cases with reduced staining, 5 of 6 had hemizygous PTEN deletion and I 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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