Characterization of human breast cancer cells affected by coculture conditions and kisspeptin-10

Characterization of human breast cancer cells affected by coculture conditions and kisspeptin-10

Elke Ziegler

Doctoral thesis

Date of Examination: 2013-06-18

Date of issue: 2013-07-04

Advisor: Gründker, Carsten Prof. Dr.

Referee: Gründker, Carsten Prof. Dr.

Referee: Dobbelstein, Matthias Prof. Dr.

Persistent Address: http://hdl.handle.net/11858/00-1735-0000-0001-BAA6-8

Files in this item

Name: Thesis-EZ-SUB.pdf

Size: 1,8 MB

Format: PDF

View/Open

The following license files are associated with this item:

Creative Commons

Abstract

English

Breast cancer is the most common type of cancer in women. Lethality is mainly attributed to a severe metastatic spread in patients. Research in new therapeutic treatments demands the understanding of the metastatic processes and the interaction of tumor cells with the distant organ microenvironment. Therefore, a coculture cell system was studied on relations between human breast cancer cells and osteoblast-like osteosarcoma cells mimicking an important metastasis environment in bone. Kisspeptin-10, a peptide derived from the metastasis suppressor gene KISS1, interferes within this cell system by inhibition of invasion. An in fluence of kisspeptin-10 in vivo was further investigated to evaluate its eff ect as a possible therapeutic option in the metastatic breast cancer disease. Human breast cancer cells were classi ed by morphology, motility marker expression and their individual invasiveness. In coculture, epithelial-like cells showed a dramatic increase in invasion. Microarray gene analysis revealed potential factors of cell motility processes and immune response mechanisms, which were regulated by the interaction of breast cancer cells and osteosarcoma cells. An involvement of EMT was shown partially by upregulation of mesenchymal gene markers without an altered epithelial marker expression. CXCL12 was identifi ed as one important factor in invasive progression: the coculture e ffect may trigger invasion by an autocrine CXCL12/CXCR4 loop. Factors as EGF and interferons are possible new targets of investigations on the interaction of breast cancer cells and osteosarcoma cells. Kisspeptin-10 was studied in breast cancer xenografts for an infl uence on metastatic spread and tumor growth. Treatment with the peptide inhibited tumor growth. But investigations on cell proliferation in vitro revealed no antiproliferative eft ect. The role of kisspeptin-10 in angiogenetic processes is an interesting option as possible mechanism leading to decreased tumor size in treated animals. A conclusion could not be o ffered on an antimetastatic e ffect of kisspeptin-10 as possible therapeutic option in breast cancer based on the poor metastasis model in mice.

Keywords: breast cancer; metastasis; coculture; KISS1; kisspeptin-10