ERβ1 Sensitizes and ERβ2 Desensitizes ERα-Positive Breast Cancer Cells to the Inhibitory Effects of Tamoxifen, Fulvestrant and Their Combination with All-Trans Retinoic Acid
Adjuvant endocrine therapy (AET) is the treatment of choice for early-stage estrogen receptor alpha (ERα)-positive breast cancer (BC). However, almost 40% of tamoxifen-treated cases display no response or a partial response to AET, thus increasing the need for new treatment options and strong predic...
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MDPI AG
2023-02-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/4/3747 |
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| author | Aggeliki K. Meligova Dimitra Siakouli Sotiria Stasinopoulou Despoina S. Xenopoulou Maria Zoumpouli Vassiliki Ganou Eleni-Fani Gkotsi Aristotelis Chatziioannou Olga Papadodima Eleftherios Pilalis Michael N. Alexis Dimitra J. Mitsiou |
| author_facet | Aggeliki K. Meligova Dimitra Siakouli Sotiria Stasinopoulou Despoina S. Xenopoulou Maria Zoumpouli Vassiliki Ganou Eleni-Fani Gkotsi Aristotelis Chatziioannou Olga Papadodima Eleftherios Pilalis Michael N. Alexis Dimitra J. Mitsiou |
| author_sort | Aggeliki K. Meligova |
| collection | DOAJ |
| description | Adjuvant endocrine therapy (AET) is the treatment of choice for early-stage estrogen receptor alpha (ERα)-positive breast cancer (BC). However, almost 40% of tamoxifen-treated cases display no response or a partial response to AET, thus increasing the need for new treatment options and strong predictors of the therapeutic response of patients at high risk of relapse. In addition to ERα, BC research has focused on ERβ1 and ERβ2 (isoforms of ERβ), the second ER isotype. At present, the impact of ERβ isoforms on ERα-positive BC prognosis and treatment remains elusive. In the present study, we established clones of MCF7 cells constitutively expressing human ERβ1 or ERβ2 and investigated their role in the response of MCF7 cells to antiestrogens [4-hydroxytamoxifen (OHΤ) and fulvestrant (ICI182,780)] and retinoids [all-trans retinoic acid (ATRA)]. We show that, compared to MCF7 cells, MCF7-ERβ1 and MCF7-ERβ2 cells were sensitized and desensitized, respectively, to the antiproliferative effect of the antiestrogens, ATRA and their combination and to the cytocidal effect of the combination of OHT and ATRA. Analysis of the global transcriptional changes upon OHT–ATRA combinatorial treatment revealed uniquely regulated genes associated with anticancer effects in MCF7-ERβ1 cells and cancer-promoting effects in MCF7-ERβ2 cells. Our data are favorable to ERβ1 being a marker of responsiveness and ERβ2 being a marker of resistance of MCF7 cells to antiestrogens alone and in combination with ATRA. |
| first_indexed | 2024-03-11T08:42:31Z |
| format | Article |
| id | doaj.art-f8b6164dfed14d41bedc2b1c88b2aaeb |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T08:42:31Z |
| publishDate | 2023-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-f8b6164dfed14d41bedc2b1c88b2aaeb2023-11-16T21:04:25ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-02-01244374710.3390/ijms24043747ERβ1 Sensitizes and ERβ2 Desensitizes ERα-Positive Breast Cancer Cells to the Inhibitory Effects of Tamoxifen, Fulvestrant and Their Combination with All-Trans Retinoic AcidAggeliki K. Meligova0Dimitra Siakouli1Sotiria Stasinopoulou2Despoina S. Xenopoulou3Maria Zoumpouli4Vassiliki Ganou5Eleni-Fani Gkotsi6Aristotelis Chatziioannou7Olga Papadodima8Eleftherios Pilalis9Michael N. Alexis10Dimitra J. Mitsiou11Institute of Chemical Biology, National Hellenic Research Foundation, 11635 Athens, GreeceInstitute of Chemical Biology, National Hellenic Research Foundation, 11635 Athens, GreeceInstitute of Chemical Biology, National Hellenic Research Foundation, 11635 Athens, GreeceInstitute of Chemical Biology, National Hellenic Research Foundation, 11635 Athens, GreeceInstitute of Chemical Biology, National Hellenic Research Foundation, 11635 Athens, GreeceInstitute of Chemical Biology, National Hellenic Research Foundation, 11635 Athens, GreeceInstitute of Chemical Biology, National Hellenic Research Foundation, 11635 Athens, GreeceCenter of Systems Biology, Biomedical Research Foundation of the Academy of Athens, 11527 Athens, GreeceInstitute of Chemical Biology, National Hellenic Research Foundation, 11635 Athens, Greecee-NIOS Applications PC, 25 Alexandros Pantou str., 17671 Kallithea, GreeceInstitute of Chemical Biology, National Hellenic Research Foundation, 11635 Athens, GreeceInstitute of Chemical Biology, National Hellenic Research Foundation, 11635 Athens, GreeceAdjuvant endocrine therapy (AET) is the treatment of choice for early-stage estrogen receptor alpha (ERα)-positive breast cancer (BC). However, almost 40% of tamoxifen-treated cases display no response or a partial response to AET, thus increasing the need for new treatment options and strong predictors of the therapeutic response of patients at high risk of relapse. In addition to ERα, BC research has focused on ERβ1 and ERβ2 (isoforms of ERβ), the second ER isotype. At present, the impact of ERβ isoforms on ERα-positive BC prognosis and treatment remains elusive. In the present study, we established clones of MCF7 cells constitutively expressing human ERβ1 or ERβ2 and investigated their role in the response of MCF7 cells to antiestrogens [4-hydroxytamoxifen (OHΤ) and fulvestrant (ICI182,780)] and retinoids [all-trans retinoic acid (ATRA)]. We show that, compared to MCF7 cells, MCF7-ERβ1 and MCF7-ERβ2 cells were sensitized and desensitized, respectively, to the antiproliferative effect of the antiestrogens, ATRA and their combination and to the cytocidal effect of the combination of OHT and ATRA. Analysis of the global transcriptional changes upon OHT–ATRA combinatorial treatment revealed uniquely regulated genes associated with anticancer effects in MCF7-ERβ1 cells and cancer-promoting effects in MCF7-ERβ2 cells. Our data are favorable to ERβ1 being a marker of responsiveness and ERβ2 being a marker of resistance of MCF7 cells to antiestrogens alone and in combination with ATRA.https://www.mdpi.com/1422-0067/24/4/3747breast cancerERβ1ERβ2prognostic markerstamoxifenICI182,780 |
| spellingShingle | Aggeliki K. Meligova Dimitra Siakouli Sotiria Stasinopoulou Despoina S. Xenopoulou Maria Zoumpouli Vassiliki Ganou Eleni-Fani Gkotsi Aristotelis Chatziioannou Olga Papadodima Eleftherios Pilalis Michael N. Alexis Dimitra J. Mitsiou ERβ1 Sensitizes and ERβ2 Desensitizes ERα-Positive Breast Cancer Cells to the Inhibitory Effects of Tamoxifen, Fulvestrant and Their Combination with All-Trans Retinoic Acid International Journal of Molecular Sciences breast cancer ERβ1 ERβ2 prognostic markers tamoxifen ICI182,780 |
| title | ERβ1 Sensitizes and ERβ2 Desensitizes ERα-Positive Breast Cancer Cells to the Inhibitory Effects of Tamoxifen, Fulvestrant and Their Combination with All-Trans Retinoic Acid |
| title_full | ERβ1 Sensitizes and ERβ2 Desensitizes ERα-Positive Breast Cancer Cells to the Inhibitory Effects of Tamoxifen, Fulvestrant and Their Combination with All-Trans Retinoic Acid |
| title_fullStr | ERβ1 Sensitizes and ERβ2 Desensitizes ERα-Positive Breast Cancer Cells to the Inhibitory Effects of Tamoxifen, Fulvestrant and Their Combination with All-Trans Retinoic Acid |
| title_full_unstemmed | ERβ1 Sensitizes and ERβ2 Desensitizes ERα-Positive Breast Cancer Cells to the Inhibitory Effects of Tamoxifen, Fulvestrant and Their Combination with All-Trans Retinoic Acid |
| title_short | ERβ1 Sensitizes and ERβ2 Desensitizes ERα-Positive Breast Cancer Cells to the Inhibitory Effects of Tamoxifen, Fulvestrant and Their Combination with All-Trans Retinoic Acid |
| title_sort | erβ1 sensitizes and erβ2 desensitizes erα positive breast cancer cells to the inhibitory effects of tamoxifen fulvestrant and their combination with all trans retinoic acid |
| topic | breast cancer ERβ1 ERβ2 prognostic markers tamoxifen ICI182,780 |
| url | https://www.mdpi.com/1422-0067/24/4/3747 |
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