Overexpression of the wild type p73 gene in breast cancer tissues and cell lines

Alexander Zaika, Sergey Kovalev, Natalie D. Marchenko, Ute M. Moll

Research output: Contribution to journalArticle

178 Citations (Scopus)

Abstract

The p73 gene is a structural and, in overexpression systems, functional p53 homologue. Ectopic p73 expression can activate a broad subset of p53- responsive genes, induce apoptosis, and act as a growth suppressor. Yet, vital oncoproteins that antagonize p53 (adenovirus E1B 55K, SV40 large T, and human papillomavirus E6) do not antagonize p73. This could suggest that inactivation of p73, in contrast to p53, is not required for tumorigenesis. Also, p73 is not activated by DNA damage. Because intragenic p73 mutations in tumors have not been reported and imprinting is idiosyncratic, tumor-specific changes in wild-type p73 expression levels become the most reliable guide toward identifying the normal function of p73 and its role in tumorigenesis. We analyzed 77 invasive breast cancers and 7 breast cancer cell lines for p73 mRNA expression levels, allelic origin, intragenic mutations, and COOH- terminal splice variants. A range of normal tissues, including breast, showed very low p73 expression, with little variation from tissue to tissue. In contrast, 38% (29 cases) of breast cancers had elevated p73 mRNA ranging from 5-25-fold above normal, with the remaining tumors (64%) falling within the normal range. Moreover, five of seven cell lines (71%) also exhibited p73 overexpression (13-73-fold). Yet, no correlation with p21 mRNA and protein levels was present, although four of the five lines were mutant for p53. Mutation analysis of the eight highest expressers showed wild type status. Eight of 14 informative samples were biallelic, whereas the remaining 6 samples showed monoallelic expression. Tumors and cell lines with p73 overexpression tended to exhibit a complex profile of up to six different COOH-terminal splice variants, whereas normal and transformed tissues with low p73 mRNA predominantly expressed p73 α. We confirm the previously described variants p73 γ and δ in breast tissue and describe two novel isoforms, p73 ε and φ, thereby further enlarging combinatorial possibilities. Together, our in vivo data show that p73 does not have a role as a classic Knudson-type tumor suppressor in breast cancer.

Original languageEnglish (US)
Pages (from-to)3257-3263
Number of pages7
JournalCancer Research
Volume59
Issue number13
StatePublished - Jul 1 1999
Externally publishedYes

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Breast Neoplasms
Cell Line
Messenger RNA
Genes
Mutation
Neoplasms
Carcinogenesis
Reference Values
Breast
Tumor Suppressor Protein p53
p53 Genes
Tumor Cell Line
Adenoviridae
DNA Damage
Protein Isoforms
Apoptosis
Growth
Proteins

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Zaika, A., Kovalev, S., Marchenko, N. D., & Moll, U. M. (1999). Overexpression of the wild type p73 gene in breast cancer tissues and cell lines. Cancer Research, 59(13), 3257-3263.

Overexpression of the wild type p73 gene in breast cancer tissues and cell lines. / Zaika, Alexander; Kovalev, Sergey; Marchenko, Natalie D.; Moll, Ute M.

In: Cancer Research, Vol. 59, No. 13, 01.07.1999, p. 3257-3263.

Research output: Contribution to journalArticle

Zaika, A, Kovalev, S, Marchenko, ND & Moll, UM 1999, 'Overexpression of the wild type p73 gene in breast cancer tissues and cell lines', Cancer Research, vol. 59, no. 13, pp. 3257-3263.
Zaika A, Kovalev S, Marchenko ND, Moll UM. Overexpression of the wild type p73 gene in breast cancer tissues and cell lines. Cancer Research. 1999 Jul 1;59(13):3257-3263.
Zaika, Alexander ; Kovalev, Sergey ; Marchenko, Natalie D. ; Moll, Ute M. / Overexpression of the wild type p73 gene in breast cancer tissues and cell lines. In: Cancer Research. 1999 ; Vol. 59, No. 13. pp. 3257-3263.
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abstract = "The p73 gene is a structural and, in overexpression systems, functional p53 homologue. Ectopic p73 expression can activate a broad subset of p53- responsive genes, induce apoptosis, and act as a growth suppressor. Yet, vital oncoproteins that antagonize p53 (adenovirus E1B 55K, SV40 large T, and human papillomavirus E6) do not antagonize p73. This could suggest that inactivation of p73, in contrast to p53, is not required for tumorigenesis. Also, p73 is not activated by DNA damage. Because intragenic p73 mutations in tumors have not been reported and imprinting is idiosyncratic, tumor-specific changes in wild-type p73 expression levels become the most reliable guide toward identifying the normal function of p73 and its role in tumorigenesis. We analyzed 77 invasive breast cancers and 7 breast cancer cell lines for p73 mRNA expression levels, allelic origin, intragenic mutations, and COOH- terminal splice variants. A range of normal tissues, including breast, showed very low p73 expression, with little variation from tissue to tissue. In contrast, 38{\%} (29 cases) of breast cancers had elevated p73 mRNA ranging from 5-25-fold above normal, with the remaining tumors (64{\%}) falling within the normal range. Moreover, five of seven cell lines (71{\%}) also exhibited p73 overexpression (13-73-fold). Yet, no correlation with p21 mRNA and protein levels was present, although four of the five lines were mutant for p53. Mutation analysis of the eight highest expressers showed wild type status. Eight of 14 informative samples were biallelic, whereas the remaining 6 samples showed monoallelic expression. Tumors and cell lines with p73 overexpression tended to exhibit a complex profile of up to six different COOH-terminal splice variants, whereas normal and transformed tissues with low p73 mRNA predominantly expressed p73 α. We confirm the previously described variants p73 γ and δ in breast tissue and describe two novel isoforms, p73 ε and φ, thereby further enlarging combinatorial possibilities. Together, our in vivo data show that p73 does not have a role as a classic Knudson-type tumor suppressor in breast cancer.",
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