Tamoxifen Treatment in Correlation with Increased ET-1 Levels Is Associated with the Development of Breast Cancer Metastases

Breast cancer is a hormone-dependent tumor. Apart from chemotherapy, a hormone-therapy is a frequently elected treatment method for patients with positive estrogen receptor status. One important drug for hormone-therapy is Tamoxifen (Tam). Tam binds to both estrogen receptors (alpha and beta) and inhibits the production of specific target genes, important for tumor development.

Endothelin-1 (ET-1), first described as a vasoconstrictor peptide, is also frequently associated with the development of tumors. ET-1 binds via two independent receptors A and B and the expression of these receptors plays an important role in the development of tumors.

The authors in this article analyzed the relationship between Tamoxifen, ET-1 overexpression, and estrogen receptor (ER) leading to Tamoxifen resistance. Breast cancer cell lines were treated with Tamoxifen, ET-1, estrogen and combinations. Using qRT-PCR, immune-precipitation, Western blot, EMSA and immunohistology target gene expression and ER complex partners were investigated. Human biopsies and mastectomy specimens were immunohistologically studied for Vimentin 3, and ERβ. 

The results indicated that breast cancer cells stimulated with a combination of Tamoxifen and ET-1 downregulate ERα, while upregulating intracellular ET-1, and ERβ. Immunoprecipation of nuclear extracts with ET-1, ERα or ERβ agarose conjugated antibodies revealed a complex formation change replacing ERα by ERβ once Tamoxifen formed a complex with ET-1. ERβ and ET-1 migrated into the nucleus. ET-1 stimulation upregulated metastases promoting target genes (IL-6, Wnt11), including a novel one, Vimentin 3. Tissue analyses showed Vim3 and ERβ expression in metastases of ERα positive breast cancer, and in ERα negative biopsies/mastectomy specimens. 

From the observations, it can be concluded that in within the limitations of such a study, ERß seems to be a more important player in ERα positive but also in ERα negative breast cancer, irrespective of the reason for this negativity. The observation of ERß and Vim3 positive tumor parallel the results from the cell culture study, suggesting that the translocation of ET-1 into the nucleus via ERß is responsible for the overproduction of Vim3, which may well be important for cells to lose their anchorage, and leave the cell layer. In short, this concept presents a new treatment approach for individualized medicine in breast cancer patients with increased ET-1 levels.

Article by Melanie von Brandenstein, et al, from Germany and UK.

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