CYR61 und S100A4 als Targets für die Therapie des triple-negativen Mammakarzinoms sowie des Tamoxifen-resistenten Mammakarzinoms
CYR61 and S100A4 as targets for the therapy of triple-negative breast cancer and tamoxifen-resistant breast cancer
by Silke Hüchel née Schiemann
Date of Examination:2022-05-10
Date of issue:2022-04-26
Advisor:Prof. Dr. Carsten Gründker
Referee:PD Dr. Silke Kaulfuß
Referee:Prof. Dr. Ralf Dressel
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EnglishTriple-negative breast cancer (TNBC) offers only few therapeutic options due to the lack of ERα and progesterone receptors as well as a non-existing overexpression of HER2. However, even in the case of ERα-positive breast cancer, the options for therapy can be limited by the acquired resistance to tamoxifen. Not only these reduced therapeutic options, but also the increased expression of prometastatic factors such as CYR61 and S100A4 in these carcinomas are responsible for their increased aggressiveness with regard to increased invasion, migration and metastasis rates. Among others, the TNBC cell lines HCC1806 and MDA-MB-231 were investigated in our group. Both cell lines showed high expression of CYR61 and S100A4. At the same time, they showed significantly higher invasion rates compared to ERα-positive cell lines. In the present study, it was shown that by using siRNA against CYR61 as well as S100A4, both factors were downregulated, evident by their decreased protein expression. At the same time, the invasion rate of the cell lines was also reduced. As a result, less metastasis should also be expected. ERα-positive MCF-7 WT mammary carcinoma cells have an extremely weak invasion rate. Acquired resistance to tamoxifen significantly enhanced the invasion behavior of both MCF-7 TR and MCF-7 TMX cell lines, and protein expression of CYR61 and S100A4 showed elevated levels. The invasion rate was also significantly increased. Knockdown of both prometastatic factors also resulted in a significant decrease in their expression, followed by a reduced invasion rate. CYR61-si RNA achieved a greater effect on the invasion rate with respect to tamoxifen-resistant cells in direct comparison to S100A4. However, also in the TNBC cell lines, CYR61- knock-down showed the greater effect. Overall, the prometastatic factors CYR61 and S100A4 appear to play an important role in the increased invasiveness in the TNBC cell lines and in the tamoxifen-resistant ERα-positive cells. The affected breast carcinoma cells show more aggressive behavior with increased invasion, migration, and metastasis. Downregulation of prometastatic factors results in a decreased rate of invasion. Considering the few therapeutic options in TNBC as well as tamoxifen-resistant breast carcinoma, a therapeutic intervention that reduces CYR61 and S100A4 may improve the treatability of these carcinomas in the future.
Keywords: breast cancer; CYR61 and S100A4; EMT; metastasis; siRNA; tumor