Poster abstracts

Poster number 72 submitted by David Taffany

Ets2-mediated genetic alterations to the myeloid genome throughout tumor progression

David A. Taffany (Comprehensive Cancer Center, The Ohio State University), Haritha Mathsyaraja (Comprehensive Cancer Center, The Ohio State University), Sudarshana M. Sharma (Comprehensive Cancer Center, The Ohio State University), Thierry Pecot (Comprehensive Cancer Center, The Ohio State University), Tahera Zabuawala (Comprehensive Cancer Center, The Ohio State University), Michael C. Ostrowski (Comprehensive Cancer Center, The Ohio State University)

Abstract:
Cancer metastasis remains a deadly aspect of invasive breast cancer, yet the underlying genetic impetus driving metastasis remains poorly understood. Discoveries in recent years have placed increasing emphasis on the cells of the surrounding tumor microenvironment in promoting metastasis, such as the abilities of macrophages and other myeloid cells to promote angiogenesis and potentially prime the premetastatic niche. Using transgenic mice in which the transcription factor Ets2 has been deleted specifically in the macrophage compartment, work in our lab suggests the Ets2 plays an important macrophage-specific role in breast cancer progression and metastasis by suppressing anti-angiogenic genes such as Thbs1, Thbs2, Timp1 and Timp3 through both direct repression and recruitment of histone deacetylase. Currently experiments are underway to, through gene expression analysis and chromatin immunoprecipitation combined with massively parallel sequencing (ChIP sequencing), unearth the global effects tumor presence has on the cells of the myeloid lineage and to determine how these effects may promote the spread and proliferation of metastatic tumor cells. Myeloid samples are currently being harvested from mammary gland, bone marrow and lungs of mice at one to five weeks following mammary fat pad injection of metastatic breast tumor cells, and gene expression analysis has been performed. NanoString gene expression analysis of lung tumor associated macrophages (TAMs) indicates differential expression upon Ets2 deletion of several important mediators of metastasis, including S100a8, Mmp9, and Il6, as well as key regulatory micro-RNAs such as miR-29, miR-223, and Let-7i. ChIP experiments for Ets2 and PU.1 are currently underway to further characterize the global genetic mechanisms through which these two transcription factors act together in TAMs to intitate and perpetuate pro-tumorigenic and pro-metastatic effects.

References:
Zabuawala T, Taffany DA, Sharma SM, Merchant A, Adair B, Srinivasan R, Rosol TJ, Fernandez S, Huang K, Leone G, Ostrowski MC. (2010). An ets2-driven transcriptional program in tumor-associated macrophages promotes tumor metastasis. Cancer Res 70, 1323-1333.

Keywords: breast cancer, metastasis, macrophage