Clinical significance of Akt and HER2/neu overexpression in African-American and Latina women with breast cancer.
BACKGROUND
Breast cancer patients with HER2/neu overexpression have poor outcomes with a decrease in disease-free survival (DFS) and overall survival. The biology of HER2/neu overexpression in breast tumors in African-American and Latina women is poorly understood. The purpose of this study is to understand the clinical significance of activated Akt (phospho-Akt or pAkt) expression in breast tumors from African-American and Latina patients with corresponding tissue HER2/neu overexpression. Cellular and molecular studies have shown that activation of the cell signaling phosphatidylinositol-3-kinase/Akt cascade via the HER2/neu and other receptor tyrosine kinases induces cell proliferation.


METHODS
A total of 234 African-American and Latina patients were selected retrospectively. From this group, 141 tumor tissue samples were analyzed for tissue pAkt by immunohistochemistry (IHC). This cohort consisted of 46 HER2/neu-positive (3+ by IHC) and 95 HER2/neu-negative tumors. The prognostic value of activated tissue Akt in relation to HER2/neu overexpression for DFS was determined.


RESULTS
Patients with low pAkt and HER2-negative tumors had the best DFS. As expected, HER2/neu-overexpressing tumors with low pAkt had a decrease in DFS. Similarly, those with high pAkt and HER2-negative tumors also had poor DFS. However, those with an increase in both HER2 and pAkt had the worst DFS. An increase in pAkt was significantly associated with HER2/neu-positive and lymph node-positive breast tumors. Tumors with high HER2 and high pAkt were metastatic. Multivariate analysis demonstrated that, in addition to the common risk factors such as larger tumor size, lymph node involvement, estrogen receptor/progesterone receptor-negative tumors, and HER2/neu-positive tumors, overexpression of pAkt significantly was associated with a decrease in 5-year DFS. A decrease in DFS with an increase in pAkt was observed in both HER2/neu-positive and -negative groups. However, the DFS was similar between HER2/neu-positive/pAkt-negative and HER2/neu-negative/pAkt-positive groups.


CONCLUSIONS
Our data suggest that there may be differences in tumor phenotypes within the HER2/neu-overexpressing breast cancer patients. The overexpression of pAkt may be a powerful prognostic marker for predicting DFS and overall survival of breast cancer patients.
Wu
Yanyuan
Y
Divisions of Cancer Research and Training, Hematology/Oncology, Department of Medicine, Charles R. Drew University of Medicine and Science, 1731 East 120th Street, Los Angeles, CA 90059, USA.
Mohamed
Hezla
H
Chillar
Ram
R
Ali
Ishrat
I
Clayton
Sheila
S
Slamon
Dennis
D
Vadgama
Jaydutt V
JV
D001741:Black or African American; D001943:Breast Neoplasms / Q000378:metabolism* / Q000401:mortality; D018572:Disease-Free Survival; D005260:Female; D006630:Hispanic or Latino; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis*; D016019:Survival Analysis
D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases