Nonredundant Functions for Tumor Protein D52-Like Proteins Support Specific Targeting of TPD52

Abstract

Purpose: Tumor protein D52 (TPD52 or D52) is frequently overexpressed in breast and other cancers and present at increased gene copy number. It is, however, unclear whether D52 amplification and overexpression target specific functional properties of the encoded protein.Experimental Design: The expression of D52-like genes and MAL2 was compared in breast tissues using quantitative reverse transcription-PCR.The functions of human D52 and D53 genes were then compared by stable expression in BALB/c 3T3 fibroblasts and transient gene knockdown in breast carcinoma cell lines. In situ D52 and MAL2 protein expression was analyzed in breast tissue samples using tissue microarray sections. Results: The D52 (8q21.13), D54 (20q13.33), and MAL2 (8q24.12) genes were significantly overexpressed in breast cancer tissue (n = 95) relative to normal breast (n = 7; P V 0.005) unlike the D53 gene (6q22.31; P = 0.884). Subsequently, D52-expressing but not D53-expressing 3T3 cell lines showed increased proliferation and anchorage-independent growth capacity, and reduced D52 but not D53 expression in SK-BR-3 cells significantly increased apoptosis. High D52 but not MAL2 expression was significantly associated with reduced overall survival in breast carcinoma patients (log-rank test, P < 0.001; n = 357) and was an independent predictor of survival (hazard ratio, 2.274; 95% confidence interval, 1.228-4.210; P = 0.009; n = 328). Conclusion: D52 overexpression in cancer reflects specific targeting and may contribute to a more proliferative, aggressive tumor phenotype in breast cancer.

Tumor protein D52 represents a negative regulator of ATM protein levels

“…Our data here further support this prediction, with TPD52 reducing ATM levels in cell lines with varying TPD52 levels. While SK-BR-3 cells are TPD52-amplified, 25 TPD52 has been previously detected immunohistochemically at higher levels in breast cancer cells in situ, compared with SK-BR-3 cells present on the same tissue microarrays, 17 which supports the use of SK-BR-3 cells as a model for interrogating TPD52 function. Similarly, exogenous TPD52 levels achieved in the 3T3 cell lines employed in this study were comparable with those detected in MCF-7 breast cancer cells, 17 which show moderate TPD52 levels.…”

“…19 TPD52 promotes proliferation, migration/invasion, and metastasis in different cell models, 17,20,21 whereas knockdown of TPD52 induced apoptosis in breast and prostate cancer cell lines. 17,22 The underlying mechanisms are not yet fully understood, apart from the regulation of Akt/protein kinase B and Stat3/Bcl-2 signaling pathways shown in prostate cancer cell lines.…”

“…19 TPD52 promotes proliferation, migration/invasion, and metastasis in different cell models, 17,20,21 whereas knockdown of TPD52 induced apoptosis in breast and prostate cancer cell lines. 17,22 The underlying mechanisms are not yet fully understood, apart from the regulation of Akt/protein kinase B and Stat3/Bcl-2 signaling pathways shown in prostate cancer cell lines. 21,22 Studies have recently indicated a possible role of TPD52 in regulating DDR, where TPD52 levels positively correlated with G 2 chromosomal radiosensitivity in lymphocytes from women with or at risk of hereditary breast cancer.…”

“…14 Interestingly, while a number of studies have associated increased TPD52 expression with poor survival in breast [15][16][17] and prostate cancers, 18 increased TPD52 expression has been reported as a favorable independent prognostic marker in ovarian carcinoma, which is usually treated with DNA damaging agents. 19 TPD52 promotes proliferation, migration/invasion, and metastasis in different cell models, 17,20,21 whereas knockdown of TPD52 induced apoptosis in breast and prostate cancer cell lines.…”

“…TPD52 transcript and protein levels show wide variations in breast cancer samples and cell lines, 17,28,47 and as a gene amplification target, TPD52 has been predicted to acquire oncogenic functions through overexpression. Our data here further support this prediction, with TPD52 reducing ATM levels in cell lines with varying TPD52 levels.…”