Expression of FANCD2 in sporadic breast cancer and clinicopathological analysis

Abstract

FANCD2 is involved in DNA damage repair and maintenance of chromosome stability. The purpose of this study was to investigate the expression of FANCD2 in sporadic breast cancer tissues and its association with clinicopathological features. A total of 162 Chinese women with invasive breast carcinoma who had no family history in first-degree relatives and 12 normal breast tissues were examined. The expression of FANCD2 was detected by immunohistochemical staining based on a tissue microarray technique. SAS system was used to analyze the data. Twenty-one out of the 162 invasive breast cancers (13%) were negative for FANCD2. The mean percentage of FANCD2 positive cells was significantly lower in breast cancers than in controls (P<0.05). FANCD2 expression was significantly inversely associated with histological grade and TNM stage (P<0.05), but not with axillary lymph node status or other conventional prognostic markers such as ER, PR, Her-2 and PCNA (P>0.05). It was suggested that FANCD2 may play a critical role in breast carcinogenesis. It may become a valuable and independent marker for identifying women with sporadic breast cancer and evaluating the prognosis.

Keywords

FANCD2 / tissue microarray / clinicopathology / sporadic breast cancer

References

[1] KingM.C., MarksJ.H., MandellJ.B.. Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science, 2003, 302(5645): 643-646

[2] BordeleauL., PanchalS., GoodwinP.. Prognosis of BRCA-associated breast cancer: a summary of evidence. Breast Cancer Res Treat, 2010, 119(1): 13-24

[3] OliveiraA.M., RossJ.S., FletcherJ.A.. Tumor suppressor genes in breast cancer: the gatekeepers and the caretakers. Am J Clin Pathol, 2005, 124(Suppl): S16-28

[4] TsudaH.. Gene and chromosomal alterations in sporadic breast cancer: correlation with histopathological features and implications for genesis and progression. Breast Cancer, 2009, 16(3): 186-201

[5] van der GroepP., HoelzelM., BuergerH., et al.. Loss of expression of FANCD2 protein in sporadic and hereditary breast cancer. Breast Cancer Res Treat, 2008, 107(1): 41-47

[6] YoussoufianH.. Fanconi anemia and breast cancer: what’s the connection?. Nat Genet, 2001, 27(4): 352-353

[7] PackeisenJ., KorschingE., HerbstH., et al.. Demystified Tissue microarray technology. Mol Pathol, 2003, 56(4): 198-204

[8] CampR.L., NeumeisterV., RimmD.L.. A decade of tissue microarrays: progress in the discovery and validation of cancer biomarkers. J Clin Oncol, 2008, 26(34): 5630-5637

[9] VoducD., KenneyC., NielsenT.O.. Tissue microarrays in clinical oncology. Semin Radiat Oncol, 2008, 18(2): 89-97

[10] VitoloM.I., WeissM.B., SzmacinskiM., et al.. Deletion of PTEN promotes tumorigenic signaling, resistance to anoikis, and altered response to chemotherapeutic agents in human mammary epithelial cells. Cancer Res, 2009, 69(21): 8275-8283

[11] DiTullioR.A.Jr, MochanT.A., VenereM., et al.. 53BP1 functions in an ATM-dependent checkpoint pathway that is constitutively activated in human cancer. Nat Cell Biol, 2002, 4(12): 998-1002

[12] BartkovaJ., HorejsíZ., KoedK., et al.. DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis. Nature, 2005, 434(7035): 864-870

[13] BarrosoE., MilneR.L., FernándezL.P., et al.. FANCD2 associated with sporadic breast cancer risk. Carcinogenesis, 2006, 27(9): 1930-1937

[14] BarrosoE., PitaG., AriasJ.I., et al.. The Fanconi anemia family of genes and its correlation with breast cancer susceptibility and breast cancer features. Breast Cancer Res Treat, 2009, 118(3): 655-660

[15] D’AndreaA.D., GrompeM.. The Fanconi anemia/BRCA pathway. Nat Rev Cancer, 2003, 3(1): 23-34

[16] OhashiA., ZdzienickaM.Z., ChenJ., et al.. Fanconi anemia complementation group D2 (FANCD2) functions independently of BRCA2- and RAD51-associated homologous recombination in response to DNA damage. J Biol Chem, 2005, 280(15): 14 877-14 883

[17] ShenX., DoH., LiY., et al.. Recruitment of fanconi anemia and breast cancer proteins to DNA damage sites is differentially governed by replication. Mol Cell, 2009, 35(5): 716-723

[18] HoughtalingS., TimmersC., NollM., et al.. Epithelial cancer in Fanconi anemia complementation group D2 (Fancd2) knockout mice. Genes Dev, 2003, 17(16): 2021-2035

[19] LevitusM., JoenjeH., de WinterJ.P.. The Fanconi anemia pathway of genomic maintenance. Cell Oncol, 2006, 28(1–2): 3-29

[20] LingC., IshiaiM., AliA.M., et al.. FAAP100 is essential for activation of the Fanconi anemia-associated DNA damage response pathway. EMBO J, 2007, 26(8): 2104-2114

[21] HowlettN.G., HarneyJ.A., RegoM.A., et al.. Functional interaction between the Fanconi anemia D2 protein and proliferating cell nuclear antigen (PCNA) via a conserved putative PCNA interaction motif. J Biol Chem, 2009, 284(42): 28 935-28 942

[22] Garcia-HigueraI., TaniguchiT., GanesanS., et al.. Interaction of the Fanconi anemia proteins and BRCA1 in a common pathway. Mol Cell, 2001, 7(2): 249-262

[23] WangX., AndreassenP.R., D’AndreaA.D.. Functional interaction of monoubiquitinated FANCD2 and BRCA2/FANCD1 in chromatin. Mol Cell Biol, 2004, 24(13): 5850-5862

[24] TurnerN., TuttA., AshworthA.. Hallmarks of’ BRCAness’ in sporadic cancers. Nat Rev Cancer, 2004, 4(10): 814-819

[25] ChirnomasD., TaniguchiT., de la VegaM., et al.. Chemosensitization to cisplatin by inhibitors of the Fanconi anemia/BRCA pathway. Mol Cancer Ther, 2005, 5(4): 952-961

[26] LyakhovichA., SurrallesJ.. FANCD2 depletion sensitizes cancer cells repopulation ability in vitro. Cancer Lett, 2007, 256(2): 186-195

[27] PowellS.N., KachnicL.A.. Therapeutic exploitation of tumor cell defects in homologous recombination. Anticancer Agents Med Chem, 2008, 8(4): 448-460

[28] WillersH., TaghianA.G., LuoC.M., et al.. Utility of DNA repair protein foci for the detection of putative BRCA1 pathway defects in breast cancer biopsies. Mol Cancer Res, 2009, 7(8): 1304-1309