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The early placenta insulin-like growth factor (EPIL; INSL4) belongs to the relaxin like peptides of the insulin superfamily. In normal tissue EPIL is only found in human placenta whereas it is found overexpressed in a subset of human breast tumors. We have shown that the EPIL expression is correlated with a positive lymph node status and a reduced overall sur-vival of breast cancer patients especially if co-expressed with Her2/ErbB2.

In vitro elevated expression levels of EPIL increase the transendothelial invasiveness of breast cancer cells but the signaling pathways leading to the phenotype remain unknown. We have therefore established a highly invasive HER2 positive, EPIL overexpressing cell line (SK-BR-3 EPIL). These cells showed an enhanced formation of protrusions which were not observed in the control cells (SK-BR-3 neo). Proliferation assays showed that the SK-BR-3 EPIL cells grow significantly slower than the parental cell line, which is in concordance with the notion that highly motile cells show decreased mitosis rates. Furthermore a decreased sen-sitivity against the cytostatic drugs Docetaxel, Paclitaxel and CPT-11 (Irinotecan) was observed in the EPIL expressing cells.

In order to investigate which genes are involved in the observed phenotypes of SK-BR-3 EPIL cells, microarray analyses using whole genome expression microarrays were performed. A notably small set of 76 genes were found to be differentially expressed between the two cell lines. The possible candidate genes belong to several different biological pathways including development, actin reorganization and regulation of transcription. The most upregulated gene in the SK-BR-3 EPIL cells is the transcription factor GATA2 (18x). GATA2 is expressed in hematopoietic progenitors as well as in nonhematopoietic embryonic stem cells. The overex-pression of GATA2 in was confirmed by Western-blot analyses. In addition the treatment of several breast cancer cells either with a synthetic EPIL peptide or SK-BR-3 EPIL conditioned medium resulted in elevated GATA2 protein levels.

Taken together the observed phenotypes of EPIL treated cells described above are very simi-lar to the observed and estimated phenotypes of cancer progenitor cells

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA

American Association for Cancer Research
2007