Background: Currently we lack the ability to rapidly test new agents to prevent breast cancer. Targeted agents are in clinical testing for treatment of breast cancer but are not being adequately explored for prevention. This is because, without biomarkers to select women that are most likely to respond and rapidly evaluate response, Phase I/II testing of targeted agents for prevention will be too risky and expensive. Single biomarkers have been traditionally used to evaluate response to chemotherapeutic agents. However, single biomarkers may not be adequate to evaluate the complex phosphorylation network signaling events that occur during breast cancer initiation. Furthermore, emerging evidence suggests that resistance to targeted agents may occur through paradoxical activation of quiescent signaling pathway. As a result, it has become increasingly important to monitoring network signaling in women receiving targeted agents.
Targeted agents that have low-toxicity profiles and have inhibitory activity against breast cancer cell proliferation and/or invasion may show promise as a prevention agent. However, before any given targeted agent could be tested for pilot prevention trials, we first need to identify 1) signaling pathway(s) that are affected by the drug in preclinical models of breast cancer, 2) short-term and long-term consequences of treatment, 3) potential biomarker(s) to closely track response.
Methods and Results: We tested for protein network signaling in cytological specimens in women at high-risk for breast cancer. Our group used reverse-phase protein microarray (RPPM) platform to test for proteomic signatures of short-term risk to breast cancer. RPPM was developed to provide reproducible assessment of 50 phospho-proteins in 5,000 epithelial cells. Initial signature testing was performed in mammary cytology obtained from two groups of 50 high-risk women undergoing Random Periareolar Fine Needle Aspiration (RPFNA). Unsupervised heirachal clustering of RPPM proteomic analysis RPFNA aspirates from high-risk women identified three activated signaling pathways 1) Akt/mTOR/PI3K/cSrc, 2) EGRF/MEK/ERK, and 3) HER2/bcl-2.
Conclusion: Here we demonstrate our ability to identify activated phospho-protein signaling pathways in limited RPFNA cytology. The power of this approach is that we can use a combination of RPPM and RPFNA to track response to any new targeted prevention agents. Importantly, we are able to validate our proteomic signatures in parallel nanobiosensor testing of live atypical RPFNA cytology from women in our high-risk cohort.
Citation Information: Cancer Prev Res 2010;3(12 Suppl):A108.