Significance of the Fanconi anemia FANCD2 protein in sporadic and metastatic human breast cancer.

Abstract

FANCD2, a pivotal protein in the Fanconi anemia and BRCA pathway/network, is monoubiquitylated in the nucleus in response to DNA damage. This study examines the subcellular location and relationship with prognostic factors and patient survival of FANCD2 in breast cancer. Antibodies to FANCD2 were used to immunocytochemically stain 16 benign and 20 malignant breast specimens as well as 314 primary breast carcinomas to assess its association with subcellular compartment and prognostic factors using Fisher's Exact test or with patient survival over 20 years using Wilcoxon-Gehan statistics. Immunoreactive FANCD2 was found in the nucleus and cytoplasm of all 16 benign tissues, but nuclear staining was lost from a significant 19/20 malignant carcinomas (P < 0.0001). Antibodies to FANCD2 stained the cytoplasm of 196 primary carcinomas, leaving 118 as negatively stained. Negative cytoplasmic staining was significantly associated with positive staining for the metastasis-inducing proteins S100A4, S100P, osteopontin, and AGR2 (P < or = 0.002). Survival of patients with FANCD2-negative carcinomas was significantly worse (P < 0.0001) than those with positively stained carcinomas, and only 4% were alive at the census date. Multivariate regression analysis identified negative staining for cytoplasmic FANCD2 as the most significant indicator of patient death (P = 0.001). Thus FANCD2's cytoplasmic loss in the primary carcinomas may allow the selection of cells overexpressing proteins that can induce metastases before surgery.

• Authors: Philip S Rudland, Angela M Platt-Higgins, Lowri M Davies, Suzete de Silva Rudland, James B Wilson, Abdulaziz Aladwani, John H R Winstanley, Dong L Barraclough, Roger Barraclough, Christopher R West, Nigel J Jones
• Journal: The American journal of pathology (Am J Pathol) Vol. 176 Issue 6 Pg. 2935-47 (Jun 2010) ISSN: 1525-2191 [Electronic] United States
• PMID: 20363922 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• FANCD2 protein, human
• Fanconi Anemia Complementation Group D2 Protein

Topics

• Adult
• Aged
• Aged, 80 and over
• Breast Neoplasms (diagnosis, metabolism, mortality, pathology)
• Cells, Cultured
• Fanconi Anemia Complementation Group D2 Protein (metabolism)
• Female
• Humans
• Middle Aged
• Neoplasm Metastasis
• Prognosis
• Survival Rate