Τίτλος:
Estrogen receptor beta increases sensitivity to enzalutamide in androgen receptor-positive triple-negative breast cancer
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
Purpose: Androgen receptor (AR) is playing an important role in the progression of a subset of TNBC. We evaluated the impact of ERβ expression along with anti-AR drugs in AR-positive TNBC. Methods: ERβ expression was examined in AR-positive TNBC cell line using MTT assay, scratch and Annexin V-FITC assay in the presence or absence of anti-androgens. Protein levels of involved molecules were assessed using Western blot. Receptors’ localization was detected by immunofluorescence and their physical association was examined using proximity ligation assay (PLA), which enables the visualization of interacting proteins in fixed cells and tissues. Results: Transient transfection of ERβ in MDA-MB 453 AR-positive TNBC cell line significantly inhibited cell proliferation, metastatic potential and induced apoptosis. ERβ expression reversed the aggravating role of AR in both indirect and direct ways. Indirectly, ERβ decreased AR activation through the inhibition of PI3K/AKT signaling pathway. Directly, ERβ formed heterodimers with AR in MDA-MB 453 cells and in human tissue samples impeding AR from forming homodimers. Enzalutamide is a more potent anti-androgen in AR + TNBC compared to bicalutamide. ERβ expression increased the sensitivity of MDA-MB 453 cells to anti-androgens and especially to enzalutamide. The administration of enzalutamide enhanced AR:ERβ heterodimers formation increasing the anti-tumor capacity of ERβ. Conclusions: Collectively, our results provide evidence for a novel mechanism by which ERβ exerts oncosuppressive effect in AR-positive TBNC through direct and indirect interactions with AR. Moreover, ERβ expression may identify a new subset of TNBC that would respond more favorable to anti-androgens. © 2019, Springer-Verlag GmbH Germany, part of Springer Nature.
Συγγραφείς:
Anestis, A.
Sarantis, P.
Theocharis, S.
Zoi, I.
Tryfonopoulos, D.
Korogiannos, A.
Koumarianou, A.
Xingi, E.
Thomaidou, D.
Kontos, M.
Papavassiliou, A.G.
Karamouzis, M.V.
Περιοδικό:
Journal of Cancer Research and Clinical Oncology
Λέξεις-κλειδιά:
androgen receptor; bicalutamide; enzalutamide; estrogen receptor beta; heterodimer; mammalian target of rapamycin; phosphatidylinositol 3 kinase; protein kinase B; androgen receptor; antineoplastic agent; biological marker; enzalutamide; estrogen receptor beta; phenylthiohydantoin; phosphatidylinositol 3 kinase; protein binding; protein kinase B; target of rapamycin kinase, antineoplastic activity; antiproliferative activity; apoptosis; Article; cell migration; cell proliferation; cell viability; controlled study; drug sensitivity; human; human cell; human tissue; immunofluorescence test; MDA-MB-453 cell line; metastasis inhibition; metastasis potential; MTT assay; Pi3K/Akt signaling; priority journal; protein expression; transient transfection; triple negative breast cancer; Western blotting; analogs and derivatives; chemistry; drug resistance; gene expression; genetics; immunohistochemistry; metabolism; pathology; protein multimerization; signal transduction; triple negative breast cancer; tumor cell line, Antineoplastic Agents; Apoptosis; Biomarkers; Cell Line, Tumor; Cell Proliferation; Drug Resistance, Neoplasm; Estrogen Receptor beta; Gene Expression; Humans; Immunohistochemistry; Phenylthiohydantoin; Phosphatidylinositol 3-Kinases; Protein Binding; Protein Multimerization; Proto-Oncogene Proteins c-akt; Receptors, Androgen; Signal Transduction; TOR Serine-Threonine Kinases; Triple Negative Breast Neoplasms
DOI:
10.1007/s00432-019-02872-9
