TITLE:
Tamoxifen Treatment in Correlation with Increased ET-1 Levels Is Associated with the Development of Breast Cancer Metastases
AUTHORS:
Melanie von Brandenstein, Julia Straube, Christina-Maria Geisbüsch, Luka Ozretić, Yasemin Ural, Verena Kirn, Wolfram Malter, Jochen W. U. Fries
KEYWORDS:
Endothelin-1, Estrogen, Estrogen Receptors, Tamoxifen, Vimentin3
JOURNAL NAME:
Journal of Cancer Therapy,
Vol.9 No.5,
May
24,
2018
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 ERβ. Results: 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 reveals a complex formation
change replacing ERα by ERβ once
Tamoxifen forms a complex with ET-1. ERβand 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 ERβ 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 Tamoxifen, ERβ and ET-1,
whose nuclear transmigration causes an overexpression of target genes. This
mechanism may explain Tamoxifen resistance. Future pathologic analyses should
include estrogen beta receptor status as well as the ET-1 expression. This
concept presents a new treatment approach for individualized medicine in breast
cancer patients with increased ET-1 levels.