Pilot and feasibility study: Prospective proteomic profiling of mammary epithelial cells from high-risk women provides evidence of activation of pro-survival pathways

Catherine Ibarra-Drendall*, Michelle M. Troch, William T. Barry, Gloria Broadwater, Emanuel F. Petricoin, Julia Wulfkuhle, Lance A. Liotta, Siya Lem, Joseph C. Baker, Anne C. Ford, Lee G. Wilke, Carola Zalles, Nicole M. Kuderer, Abigail W. Hoffman, Melanie Shivraj, Priya Mehta, Jamila Williams, Nora Tolbert, Laurie W. Lee, Patrick G. PilieDihua Yu, Victoria L. Seewaldt

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

Normal mammary gland homeostasis requires the coordinated regulation of protein signaling networks. However, we have little prospective information on whether activation of protein signaling occurs in premalignant mammary epithelial cells, as represented by cells with cytological atypia from women who are at high risk for breast cancer. This information is critical for understanding the role of deregulated signaling pathways in the initiation of breast cancer and for developing targeted prevention and/or treatment strategies for breast cancer in the future. In this pilot and feasibility study, we examined the expression of 52 phosphorylated, total, and cleaved proteins in 31 microdissected Random Periareolar Fine Needle Aspiration (RPFNA) samples by high-throughput Reverse Phase Protein Microarray. Unsupervised hierarchical clustering analysis indicated the presence of four clusters of proteins that represent the following signaling pathways: (1) receptor tyrosine kinase/Akt/mammalian target of rapamycin (RTK/Akt/mTOR), (2) RTK/Akt/extracellular signal-regulated kinase (RTK/Akt/ERK), (3) mitochondrial apoptosis, and (4) indeterminate. Clusters 1 through 3 comprised moderately to highly expressed proteins, while Cluster 4 comprised proteins that are lowly expressed in a majority of RPFNA samples. Our exploratory study showed that the interlinked components of mitochondrial apoptosis pathway are highly expressed in all mammary epithelial cells obtained from high-risk women. In particular, the expression levels of anti-apoptotic Bcl-xL and pro-apoptotic Bad are positively correlated in both non-atypical and atypical samples (unadjusted P < 0.0001), suggesting a delicate balance between the pro-apoptotic and anti-apoptotic regulation of cell proliferation during the early steps of mammary carcinogenesis. Our feasibility study suggests that the activation of key proteins along the RTK/Akt pathway may tip this balance to cell survival. Taken together, our results demonstrate the feasibility of mapping proteomic signaling networks in limited RPFNA samples obtained from high-risk women and the promise of developing rational drug targets or preventative strategies for breast cancer in future proteomic studies with a larger cohort of high-risk women.

Original languageEnglish
Pages (from-to)487-498
Number of pages12
JournalBreast Cancer Research and Treatment
Volume132
Issue number2
DOIs
StatePublished - Apr 2012
Externally publishedYes

Keywords

  • Atypical mammary cytology
  • Biomarker development
  • Breast cancer risk
  • Cell survival
  • Protein microarray

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