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Published on: May 17, 2019
The Akt pathway in human breast cancer: a tissue-array-based analysis
Shikha Bose1, Sindhu Chandran, James M Mirocha
1Department of Pathology, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA. BoseS@cshs.org
Abstract:
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.
Insights
The Akt pathway is activated early in breast cancer, even in the in-situ stage. PTEN loss and S6 overexpression correlate with disease progression, impacting targeted therapy development.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- The Akt pathway regulates cell proliferation and survival, and its deregulation is common in cancers.
- Kinase inhibitors targeting the Akt pathway have shown promise in reducing tumor growth.
Purpose of the Study:
- To investigate the Akt pathway's status in human breast cancers.
- To examine relationships between Akt pathway component proteins and their correlation with tumor characteristics and patient outcomes.
Main Methods:
- Immunohistochemistry was used to evaluate expression levels of PTEN, phosphorylated Akt, FKHR, mTOR, S6, and cyclin D1.
- Analysis was performed on a tissue microarray of 145 invasive breast cancers and 140 ductal carcinomas in-situ.
- Statistical correlations were made between protein expression, tumor characteristics, and disease outcome.
Main Results:
- Akt pathway activation was observed early, in the in-situ stage of breast cancer.
- PTEN loss did not consistently correlate with Akt activation, suggesting alternative mechanisms.
- PTEN loss and S6 overexpression increased with disease progression from in-situ to invasive stages.
- Cyclin D1 overexpression in low-grade tumors correlated with longer disease-free survival.
- mTOR overexpression was associated with a threefold increased risk of disease recurrence.
Conclusions:
- The Akt pathway is activated early in breast cancer development.
- Aberrant expression of PTEN, S6, and mTOR are associated with breast cancer progression and recurrence risk.
- Findings support the potential of targeted therapies and highlight cyclin D1's prognostic value.
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