Abstract
Background: Currently we lack adequate prevention strategies for triple-negative breast cancer; progress in designing targeted strategies is limited by a lack of knowledge of the biology of cancer initiation. The origins of triple-negative breast cancer in premenopausal women are poorly understood. Importantly, we do not understand whether the molecular pathways that underlie the aggressive behavior of triple-negative breast cancer can be detected in premalignant breast lesions. Growing evidence indicates that early mammary carcinogenesis is regulated by integrated signaling networks and not by isolated genes. Interleukin-6 (IL6) plays a role in stem cell regeneration, promotes epithelial to mesenchymal transition (EMT), and high IL6 serum levels predict a poor outcome in premenopausal women with triple-negative breast cancer.
Methods and Results: We used Reverse-Phase Protein Microarray (RPPM) profiling to test for activation of phosphoprotein signaling in premalignant Random Periareolar Fine Needle Aspiration (RPFNA) mammary epithelial cytology from 65 high-risk African American women. Unsupervised hierarchical clustering of RPPM proteomic analysis RPFNA aspirates identified three activated ER− signaling pathways including co-activation of Akt/mTOR/PI3K and IL6/pStat3/vimentin. Analysis of interstitial breast tissue demonstrated that high interstitial IL6/VEGF cytokine production predicted high epithelial expression of pStat3/vimentin. Based on these observations we are currently launching a prevention trial to target Akt/mTor using metformin 500 mg bid.
Conclusion: This is the first demonstration that Akt/mTor and IL6/Stat3/vimentin signaling is activated in pre-cancerous mammary epithelial cells from high-risk premenopausal women. Currently we are testing whether trials are on-going to test whether metformin can inhibit activation of mammary epithelial Akt/mTor and perhaps IL6/Stat3/vimentin signaling.
Citation Information: Cancer Prev Res 2011;4(10 Suppl):CN07-03.
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