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

Abstract

Background: In breast cancer patients, a correlation between endothelin-1 (ET-1) and lymph node metastasis was found. While breast cancer with a positive ER status can be treated with Tamoxifen, several studies describe increasing Tamoxifen resistance in patients. We analyzed the relationship between Tamoxifen, ET-1 overexpression, and ER leading to Tamoxifen resistance. Methods: 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 ERß. Results: Breast cancer cells stimulated with a combination of Tamoxifen and ET-1 downregulate ERα, while upregulating intracellular ET-1, and ERß. Immunoprecipation of nuclear extracts with ET-1, ERα or ERß agarose conjugated antibodies reveals a complex formation change replacing ERα by ERß once Tamoxifen forms a complex with ET-1. ERß and ET-1 migrate into the nucleus. ET-1 stimulation upregulates metastases promoting target genes (IL-6, Wnt11), including a novel one, Vimentin 3. Tissue analyses show Vim3 and ERß expression in metastases of ERα positive breast cancer, and in ERα negative biopsies/mastectomy specimens. Conclusion: We are the first to describe a complex consisting of How to cite this paper: von Brandenstein,

Vimentin 3 Expression in Prostate Cancer Cells

“…A clear correlation between the overexpression of ET-1 and the production of a truncated Vimentin version, called Vim3, was recently described (7). Due to this truncation of Vimentin, cells lose their normal cell structure, as full-length Vimentin (VimFL) is important for the arrangement of cell organelles and the anchorage of cells (8).…”