Death-associated protein kinase loss of expression is a new marker for breast cancer prognosis.
OBJECTIVE
Death-associated protein (DAP)-kinase is a new Ser/Thr kinase involved in cell apoptosis and tumor suppression, the expression of which has been correlated to invasive potential and metastasis in several human neoplastic tissues. We analyzed the level of DAP-kinase expression in breast cancer specimens and its correlation with survival.


METHODS
One hundred twenty-eight breast cancer specimens were analyzed by immunohistochemistry. Patient records were studied retrospectively for demographic characteristics, clinical data, hormonal treatment, outcome, and survival. DAP-kinase protein expression was also studied in normal breast cells primary cultures under estrogen and antiestrogen treatment.


RESULTS
Among the 128 patients, 30 showed a DAP-kinase staining < or = 20%, whereas 98 had a staining over 20%. Mean follow-up time was 62 months. The association between tumor Scarff-Bloom and Richardson grade (P = 0.009), estrogen receptor and progesterone receptor expression (P = 0.002 and 0.001, respectively), tumor size (P = 0.05), Bcl-2 expression (P = 0.004), and DAP-kinase immunostaining in the ductal carcinoma group was highly significant. Overall (64 months) and disease-free (63 months) survival in the high DAP-kinase expression group were significantly longer compared with the women whose tumors showed a loss of DAP-kinase expression (51 and 43 months, respectively). DAP-kinase protein was strongly expressed in normal breast tissue and in human breast epithelial cells primary cultures. Estradiol decreased DAP-kinase expression in these cells, arguing for hormonal regulation of the protein.


CONCLUSIONS
Loss of DAP-kinase expression negatively correlates to survival and positively correlates to the probability of recurrence in a very significant manner. DAP-kinase thus constitutes a novel and independent prognosis marker for breast cancer.
Lévy
Delphine
D
Unité de Gynécologie Endocrinienne, Hôpital Hôtel Dieu, Paris, France.
Plu-Bureau
Geneviève
G
Decroix
Yves
Y
Hugol
Danielle
D
Rostène
William
W
Kimchi
Adi
A
Gompel
Anne
A
D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins; D014408:Biomarkers, Tumor / Q000096:biosynthesis; D001940:Breast / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000096:biosynthesis*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D064550:Death-Associated Protein Kinases; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D020847:Estrogen Receptor Modulators / Q000494:pharmacology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D011379:Prognosis; D016016:Proportional Hazards Models; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D011960:Receptors, Estrogen / Q000032:analysis; D011980:Receptors, Progesterone / Q000032:analysis; D016019:Survival Analysis; D013629:Tamoxifen / Q000627:therapeutic use; D005466:Fluorocarbons
D018931:Antineoplastic Agents, Hormonal; D051017:Apoptosis Regulatory Proteins; D014408:Biomarkers, Tumor; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D064550:Death-Associated Protein Kinases; D004958:Estradiol; D020847:Estrogen Receptor Modulators; D019253:Proto-Oncogene Proteins c-bcl-2; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D013629:Tamoxifen; C086511:RU 58668; D005466:Fluorocarbons