The Akt pathway, an important regulator of cell proliferation and survival, is deregulated in many
cancers. The pathway has achieved considerable importance due to the development of
kinase inhibitors that are able to successfully reduce
tumor growth. This study was conducted to determine the status of the Akt pathway in human breast
cancers and to study the relationship between the different component
proteins. Expression levels of PTEN, phosphorylated forms of the constituent
proteins (Akt, FKHR, mTOR, and S6) and
cyclin D1 were evaluated by immunohistochemistry, on consecutive sections from a tissue microarray containing 145 invasive breast
cancers and 140 pure
ductal carcinomas in-situ. Aberrant expression was correlated statistically with
tumor characteristics and disease outcome. The Akt pathway was found to be activated early in
breast cancer, in the in-situ stage. In all, 33, 15, 32, and 60% of
ductal carcinoma in-situ showed overexpression of Akt, FKHR, mTOR, and
cyclin D1. PTEN loss did not correlate statistically with expression of AKT or any of the other
proteins with the exception of S6, indicating that Akt activation was not a result of PTEN loss. Expression levels of PTEN and S6 were significantly different in in-situ and invasive
cancers, indicating association with
disease progression. Loss of PTEN was noted in 11% of in-situ as compared to 26% of invasive
cancers, while S6 overexpression was seen in 47% in-situ and in 72% invasive
cancers. High-grade
carcinomas were associated with PTEN loss, while low-grade
carcinomas with good prognostic features showed
cyclin D1 overexpression and were associated with longer disease free survival. Additionally,
cancers with mTOR overexpression showed a three times greater risk for disease recurrence. Overall, a large proportion of in-situ and invasive breast
cancers overexpressed cyclinD1 and S6. Our results may have significant implications in the development and application of targeted
therapy.