FP16-5 Proteomic Signatures of Acquired Letrozole Resistance in Breast Cancer: Suppressed Estrogen Signaling and Increased Cell Motility and Invasiveness

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: FP16-Cancers of Endocrine Organs: Mechanisms of Tumorigenesis & Progression
Sunday, June 16, 2013: 10:45 AM-11:15 AM
Presentation Start Time: 11:05 AM
Room 206 (Moscone Center)

Poster Board SUN-294
Syreeta L Tilghman*1, Ian Townley1, Jin Zou1, Shawn Dion Llopis1, Patrick Carriere1, Lynez Preyan1, Christopher C Williams1, Elena Skripnikova1, Qiang Zhang2, Melyssa R Bratton1 and Guangdi Wang2
1Xavier University of Louisiana, College of Pharmacy, New Orleans, LA, 2Xavier University of Louisiana, New Orleans, LA
Aromatase inhibitors (AIs), such as letrozole, have become the first line treatment for postmenopausal women with estrogen-dependent breast cancer.  However, acquired resistance remains a major clinical obstacle.  Previous studies demonstrated constitutive activation of the MAPK signaling, overexpression of HER2, and downregulation of aromatase and ERα in letrozole-resistant breast cancer cells.  Given the complex signaling network involved in letrozole-refractory breast cancer and the lack of effective treatment for hormone resistance, further investigation of AI resistance by a novel systems biology approach may reveal previously unconsidered molecular changes that could be utilized as therapeutic targets.  This study was undertaken to characterize for the first time global proteomic alterations occurring in a letrozole-resistant cell line.  A quantitative proteomic analysis of the whole cell lysates of LTLT-Ca (resistant) vs. AC-1 cells (sensitive) was performed to identify significant protein expression changes.  A total of 1743 proteins were identified and quantified, of which 411 were significantly upregulated and 452 significantly downregulated (p<0.05, fold change > 1.20).  Bioinformatics analysis revealed that acquired letrozole resistance is associated with a hormone-independent, more aggressive phenotype.  LTLT-Ca cells exhibited 84% and 138% increase in migration and invasion compared to the control cells.  The ROCK inhibitor partially abrogated the enhanced migration and invasion of the letrozole-resistant cells.  Flow cyotmetric analyses also demonstrated an increase in vimentin expression in letrozole-resistance cells, suggesting an onset of epithelial to mesenchymal transition (EMT).  Moreover, targeted gene expression arrays confirmed a 28-fold and 6-fold upregulation of EGFR and HER2, respectively, while ERα and pS2 were dramatically reduced by 28-fold and 1100-fold, respectively.  Taken together, our study revealed global proteomic signatures of a letrozole-resistant cell line associated with hormone independence, enhanced cell motility, EMT and the potential values of several altered proteins as novel prognostic markers or therapeutic targets for letrozole resistant breast cancer.

Nothing to Disclose: SLT, IT, JZ, SDL, PC, LP, CCW, ES, QZ, MRB, GW

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: Louisiana Cancer Research Consortium NIH-RCMI grant #5G12RR026260