The ERRα–VDR axis promotes calcitriol degradation and estrogen signaling in breast cancer cells, while VDR‐CYP24A1‐ERRα overexpression correlates with poor prognosis in patients with basal‐like breast cancer
Vitamin D is used to reduce cancer risk and improve the outcome of cancer patients, but the vitamin D receptor (VDR; also known as the calcitriol receptor) pathway needs to be functionally intact to ensure the biological effects of circulating calcitriol, the active form of vitamin D. Besides estrog...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2022-02-01
|
| Series: | Molecular Oncology |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/1878-0261.13013 |
| _version_ | 1818282361117212672 |
|---|---|
| author | Katia Danza Letizia Porcelli Simona De Summa Roberta Di Fonte Brunella Pilato Rosanna Lacalamita Simona Serratì Amalia Azzariti Stefania Tommasi |
| author_facet | Katia Danza Letizia Porcelli Simona De Summa Roberta Di Fonte Brunella Pilato Rosanna Lacalamita Simona Serratì Amalia Azzariti Stefania Tommasi |
| author_sort | Katia Danza |
| collection | DOAJ |
| description | Vitamin D is used to reduce cancer risk and improve the outcome of cancer patients, but the vitamin D receptor (VDR; also known as the calcitriol receptor) pathway needs to be functionally intact to ensure the biological effects of circulating calcitriol, the active form of vitamin D. Besides estrogen receptor alpha (ERα), estrogen‐related receptor alpha (ERRα) has also been shown to interfere with the VDR pathway, but its role in the antitumor and transactivation activity of calcitriol is completely unknown in breast cancer (BC). We observed that ERRα functionally supported the proliferation of BC cell lines and acted as a calcitriol‐induced regulator of VDR. As such, ERRα deregulated the calcitriol–VDR transcription by enhancing the expression of CYP24A1 as well as of both ERα and aromatase (CYP19A1) in calcitriol‐treated cells. ERRα knockdown limited the effect of calcitriol by reducing calcitriol‐induced G0/G1 phase cell cycle arrest and by affecting the expression of cyclin D1 and p21/Waf. The interactome analysis suggested that Peroxisome Proliferator‐Activated Receptor Gamma Coactivator 1‐α (PGC‐1α) and Proline‐, glutamic acid‐, and leucine‐rich protein 1 (PELP1) are key players in the genomic actions of the calcitriol–VDR–ERRα axis. Evaluation of patient outcomes in The Cancer Genome Atlas (TCGA) dataset showed the translational significance of the biological effects of the VDR–ERRα axis, highlighting that VDR, CYP24A1, and ERRα overexpression correlates with poor prognosis in basal‐like BC. |
| first_indexed | 2024-12-13T00:19:47Z |
| format | Article |
| id | doaj.art-4a3c78e8a74c4d76a4b251811673088b |
| institution | Directory Open Access Journal |
| issn | 1574-7891 1878-0261 |
| language | English |
| last_indexed | 2024-12-13T00:19:47Z |
| publishDate | 2022-02-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Oncology |
| spelling | doaj.art-4a3c78e8a74c4d76a4b251811673088b2022-12-22T00:05:38ZengWileyMolecular Oncology1574-78911878-02612022-02-0116490492010.1002/1878-0261.13013The ERRα–VDR axis promotes calcitriol degradation and estrogen signaling in breast cancer cells, while VDR‐CYP24A1‐ERRα overexpression correlates with poor prognosis in patients with basal‐like breast cancerKatia Danza0Letizia Porcelli1Simona De Summa2Roberta Di Fonte3Brunella Pilato4Rosanna Lacalamita5Simona Serratì6Amalia Azzariti7Stefania Tommasi8Molecular Diagnostics and Pharmacogenetics Unit IRCCS Istituto Tumori Giovanni Paolo II Bari ItalyLaboratory of Experimental Pharmacology IRCCS Istituto Tumori Giovanni Paolo II Bari ItalyMolecular Diagnostics and Pharmacogenetics Unit IRCCS Istituto Tumori Giovanni Paolo II Bari ItalyLaboratory of Experimental Pharmacology IRCCS Istituto Tumori Giovanni Paolo II Bari ItalyMolecular Diagnostics and Pharmacogenetics Unit IRCCS Istituto Tumori Giovanni Paolo II Bari ItalyMolecular Diagnostics and Pharmacogenetics Unit IRCCS Istituto Tumori Giovanni Paolo II Bari ItalyLaboratory of Nanotechnology IRCCS Istituto Tumori Giovanni Paolo II Bari ItalyLaboratory of Experimental Pharmacology IRCCS Istituto Tumori Giovanni Paolo II Bari ItalyMolecular Diagnostics and Pharmacogenetics Unit IRCCS Istituto Tumori Giovanni Paolo II Bari ItalyVitamin D is used to reduce cancer risk and improve the outcome of cancer patients, but the vitamin D receptor (VDR; also known as the calcitriol receptor) pathway needs to be functionally intact to ensure the biological effects of circulating calcitriol, the active form of vitamin D. Besides estrogen receptor alpha (ERα), estrogen‐related receptor alpha (ERRα) has also been shown to interfere with the VDR pathway, but its role in the antitumor and transactivation activity of calcitriol is completely unknown in breast cancer (BC). We observed that ERRα functionally supported the proliferation of BC cell lines and acted as a calcitriol‐induced regulator of VDR. As such, ERRα deregulated the calcitriol–VDR transcription by enhancing the expression of CYP24A1 as well as of both ERα and aromatase (CYP19A1) in calcitriol‐treated cells. ERRα knockdown limited the effect of calcitriol by reducing calcitriol‐induced G0/G1 phase cell cycle arrest and by affecting the expression of cyclin D1 and p21/Waf. The interactome analysis suggested that Peroxisome Proliferator‐Activated Receptor Gamma Coactivator 1‐α (PGC‐1α) and Proline‐, glutamic acid‐, and leucine‐rich protein 1 (PELP1) are key players in the genomic actions of the calcitriol–VDR–ERRα axis. Evaluation of patient outcomes in The Cancer Genome Atlas (TCGA) dataset showed the translational significance of the biological effects of the VDR–ERRα axis, highlighting that VDR, CYP24A1, and ERRα overexpression correlates with poor prognosis in basal‐like BC.https://doi.org/10.1002/1878-0261.13013breast cancercalcitriolCYP24A1ERRαVDR |
| spellingShingle | Katia Danza Letizia Porcelli Simona De Summa Roberta Di Fonte Brunella Pilato Rosanna Lacalamita Simona Serratì Amalia Azzariti Stefania Tommasi The ERRα–VDR axis promotes calcitriol degradation and estrogen signaling in breast cancer cells, while VDR‐CYP24A1‐ERRα overexpression correlates with poor prognosis in patients with basal‐like breast cancer Molecular Oncology breast cancer calcitriol CYP24A1 ERRα VDR |
| title | The ERRα–VDR axis promotes calcitriol degradation and estrogen signaling in breast cancer cells, while VDR‐CYP24A1‐ERRα overexpression correlates with poor prognosis in patients with basal‐like breast cancer |
| title_full | The ERRα–VDR axis promotes calcitriol degradation and estrogen signaling in breast cancer cells, while VDR‐CYP24A1‐ERRα overexpression correlates with poor prognosis in patients with basal‐like breast cancer |
| title_fullStr | The ERRα–VDR axis promotes calcitriol degradation and estrogen signaling in breast cancer cells, while VDR‐CYP24A1‐ERRα overexpression correlates with poor prognosis in patients with basal‐like breast cancer |
| title_full_unstemmed | The ERRα–VDR axis promotes calcitriol degradation and estrogen signaling in breast cancer cells, while VDR‐CYP24A1‐ERRα overexpression correlates with poor prognosis in patients with basal‐like breast cancer |
| title_short | The ERRα–VDR axis promotes calcitriol degradation and estrogen signaling in breast cancer cells, while VDR‐CYP24A1‐ERRα overexpression correlates with poor prognosis in patients with basal‐like breast cancer |
| title_sort | errα vdr axis promotes calcitriol degradation and estrogen signaling in breast cancer cells while vdr cyp24a1 errα overexpression correlates with poor prognosis in patients with basal like breast cancer |
| topic | breast cancer calcitriol CYP24A1 ERRα VDR |
| url | https://doi.org/10.1002/1878-0261.13013 |
| work_keys_str_mv | AT katiadanza theerravdraxispromotescalcitrioldegradationandestrogensignalinginbreastcancercellswhilevdrcyp24a1erraoverexpressioncorrelateswithpoorprognosisinpatientswithbasallikebreastcancer AT letiziaporcelli theerravdraxispromotescalcitrioldegradationandestrogensignalinginbreastcancercellswhilevdrcyp24a1erraoverexpressioncorrelateswithpoorprognosisinpatientswithbasallikebreastcancer AT simonadesumma theerravdraxispromotescalcitrioldegradationandestrogensignalinginbreastcancercellswhilevdrcyp24a1erraoverexpressioncorrelateswithpoorprognosisinpatientswithbasallikebreastcancer AT robertadifonte theerravdraxispromotescalcitrioldegradationandestrogensignalinginbreastcancercellswhilevdrcyp24a1erraoverexpressioncorrelateswithpoorprognosisinpatientswithbasallikebreastcancer AT brunellapilato theerravdraxispromotescalcitrioldegradationandestrogensignalinginbreastcancercellswhilevdrcyp24a1erraoverexpressioncorrelateswithpoorprognosisinpatientswithbasallikebreastcancer AT rosannalacalamita theerravdraxispromotescalcitrioldegradationandestrogensignalinginbreastcancercellswhilevdrcyp24a1erraoverexpressioncorrelateswithpoorprognosisinpatientswithbasallikebreastcancer AT simonaserrati theerravdraxispromotescalcitrioldegradationandestrogensignalinginbreastcancercellswhilevdrcyp24a1erraoverexpressioncorrelateswithpoorprognosisinpatientswithbasallikebreastcancer AT amaliaazzariti theerravdraxispromotescalcitrioldegradationandestrogensignalinginbreastcancercellswhilevdrcyp24a1erraoverexpressioncorrelateswithpoorprognosisinpatientswithbasallikebreastcancer AT stefaniatommasi theerravdraxispromotescalcitrioldegradationandestrogensignalinginbreastcancercellswhilevdrcyp24a1erraoverexpressioncorrelateswithpoorprognosisinpatientswithbasallikebreastcancer AT katiadanza erravdraxispromotescalcitrioldegradationandestrogensignalinginbreastcancercellswhilevdrcyp24a1erraoverexpressioncorrelateswithpoorprognosisinpatientswithbasallikebreastcancer AT letiziaporcelli erravdraxispromotescalcitrioldegradationandestrogensignalinginbreastcancercellswhilevdrcyp24a1erraoverexpressioncorrelateswithpoorprognosisinpatientswithbasallikebreastcancer AT simonadesumma erravdraxispromotescalcitrioldegradationandestrogensignalinginbreastcancercellswhilevdrcyp24a1erraoverexpressioncorrelateswithpoorprognosisinpatientswithbasallikebreastcancer AT robertadifonte erravdraxispromotescalcitrioldegradationandestrogensignalinginbreastcancercellswhilevdrcyp24a1erraoverexpressioncorrelateswithpoorprognosisinpatientswithbasallikebreastcancer AT brunellapilato erravdraxispromotescalcitrioldegradationandestrogensignalinginbreastcancercellswhilevdrcyp24a1erraoverexpressioncorrelateswithpoorprognosisinpatientswithbasallikebreastcancer AT rosannalacalamita erravdraxispromotescalcitrioldegradationandestrogensignalinginbreastcancercellswhilevdrcyp24a1erraoverexpressioncorrelateswithpoorprognosisinpatientswithbasallikebreastcancer AT simonaserrati erravdraxispromotescalcitrioldegradationandestrogensignalinginbreastcancercellswhilevdrcyp24a1erraoverexpressioncorrelateswithpoorprognosisinpatientswithbasallikebreastcancer AT amaliaazzariti erravdraxispromotescalcitrioldegradationandestrogensignalinginbreastcancercellswhilevdrcyp24a1erraoverexpressioncorrelateswithpoorprognosisinpatientswithbasallikebreastcancer AT stefaniatommasi erravdraxispromotescalcitrioldegradationandestrogensignalinginbreastcancercellswhilevdrcyp24a1erraoverexpressioncorrelateswithpoorprognosisinpatientswithbasallikebreastcancer |