Role of membrane-bound estrogen receptors in Tamoxifen-resistant breast cancers
Final Report Abstract
Tamoxifen is a widely used drug to treat premenopausal women with estrogen receptorpositive breast cancer. Nevertheless, there is a risk that tumors develop resistance to this drug, leading to therapy failure in about 20% of the cases. Several investigations have been conducted to identify the molecular mechanisms underlying this tamoxifen adaption or to develop predictive markers for tamoxifen resistance. But up to now, no sufficient marker to predict tamoxifen resistance in a clinical setting has been established. Current knowledge points towards an important role of estrogen receptor expression itself and also a significant contribution of epidermal growth factor signaling to this process. As there are substantial studies published, linking alternative estrogen receptors such as the GPER1 or splice products of the classical estrogen receptor to tamoxifen resistance we attempted to analyze the impact of such membrane bound receptors, especially ERα36, further. We analyzed gene expression changes in a cell culture model simulating tamoxifen adaption, leading to clinical tamoxifen resistance. In contrast to several other studies we decided to use the active metabolite of tamoxifen, the 4OH-tamoxifen, in a low dose that can be expected to be present in treated tumors. The cells answered by immediate gene expression alterations that changed towards a stable, distinct gene expression pattern already after 4 weeks of treatment. By analyzing these gene expression changes, more than 500 genes with highly significant changes in expression could be identified. Some of these genes, including Neuronatin (NNAT) or transmembrane protein 26 (TMEM26) have been further investigated by retrospective survival analysis in our breast cancer cohort, or publicly available gene expression databases, and prognostic significance could be proven. Genetically engineered MCF-7 breast cancer cells that show enhanced expression of the estrogen receptor variant ERα36 exhibited increased proliferation and migration in-vitro. This would argue for more aggressive behavior of ERα36 expressing tumors; however immunohistochemical analysis of ERα36 in breast tumors, suggested that ERα36 expression did not result in poor prognosis. Also, such cells did not show a gene expression pattern very similar to tamoxifen adapted cells. Altogether these data suggest that ERα36, although involved in tamoxifen responses, is not the key determinant of tamoxifen resistance in patients.
Publications
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Tamoxifen resistance: From cell culture experiments towards novel biomarkers. Pathology - Research and Practice 2015pii: S0344-0338(15)00006-0
N. Nass, T. Kalinski
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Expression of transmembrane protein 26 (TMEM26) in breast cancer and its association with drug response. 2016
Nass N, Dittmer A, Hellwig V, Lange T, Beyer JM , Leyh B, Ignatov A, Weißenborn C, Kirkegaard T, Lykkesfeldt AE, Kalinski T, and Dittmer J
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Oxidative stress and glyoxalase I activity mediate dicarbonyl toxicity in MCF-7 mamma carcinoma cells and a tamoxifen resistant derivative. Biochim Biophys Acta. 2016;1860(6):1272-80
Nass N, Sel S, Ignatov A, Roessner A, Kalinski T
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Accumulation of the advanced glycation end product carboxymethyl lysine in breast cancer is positively associated with estrogen receptor expression and unfavorable prognosis in estrogen receptor-negative cases. Histochem Cell Biol. 2017 May;147(5):625-634
Nass N, Ignatov A, Andreas L, Weißenborn C, Kalinski T, Sel S
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GPER Promoter Methylation Controls GPER Expression in Breast Cancer Patients. Cancer Invest. 2017 Feb 7;35(2):100-107
Weissenborn C, Ignatov T, Nass N, Kalinski T, Dan Costa S, Zenclussen AC, Ignatov A
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High neuronatin (NNAT) expression is associated with poor outcome in breast cancer. Virchows Arch. 2017 May 24
Nass N, Walter S, Jechorek D, Weissenborn C, Ignatov A, Haybaeck J, Sel S, Kalinski T
