RANK is a poor prognosis marker and a therapeutic target in ER‐negative postmenopausal breast cancer
Abstract Despite strong preclinical data, the therapeutic benefit of the RANKL inhibitor, denosumab, in breast cancer patients, beyond the bone, is unclear. Aiming to select patients who may benefit from denosumab, we hereby analyzed RANK and RANKL protein expression in more than 2,000 breast tumors...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Springer Nature
2023-04-01
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| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/emmm.202216715 |
| _version_ | 1797280293732745216 |
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| author | Marina Ciscar Eva M Trinidad Gema Perez‐Chacon Mansour Alsaleem Maria Jimenez Maria J Jimenez‐Santos Hector Perez‐Montoyo Adrian Sanz‐Moreno Andrea Vethencourt Michael Toss Anna Petit Maria T Soler‐Monso Victor Lopez Jorge Gomez‐Miragaya Clara Gomez‐Aleza Lacey E Dobrolecki Michael T Lewis Alejandra Bruna Silvana Mouron Miguel Quintela‐Fandino Fatima Al‐Shahrour Antonio Martinez‐Aranda Angels Sierra Andrew R Green Emad Rakha Eva Gonzalez‐Suarez |
| author_facet | Marina Ciscar Eva M Trinidad Gema Perez‐Chacon Mansour Alsaleem Maria Jimenez Maria J Jimenez‐Santos Hector Perez‐Montoyo Adrian Sanz‐Moreno Andrea Vethencourt Michael Toss Anna Petit Maria T Soler‐Monso Victor Lopez Jorge Gomez‐Miragaya Clara Gomez‐Aleza Lacey E Dobrolecki Michael T Lewis Alejandra Bruna Silvana Mouron Miguel Quintela‐Fandino Fatima Al‐Shahrour Antonio Martinez‐Aranda Angels Sierra Andrew R Green Emad Rakha Eva Gonzalez‐Suarez |
| author_sort | Marina Ciscar |
| collection | DOAJ |
| description | Abstract Despite strong preclinical data, the therapeutic benefit of the RANKL inhibitor, denosumab, in breast cancer patients, beyond the bone, is unclear. Aiming to select patients who may benefit from denosumab, we hereby analyzed RANK and RANKL protein expression in more than 2,000 breast tumors (777 estrogen receptor‐negative, ER−) from four independent cohorts. RANK protein expression was more frequent in ER− tumors, where it associated with poor outcome and poor response to chemotherapy. In ER− breast cancer patient‐derived orthoxenografts (PDXs), RANKL inhibition reduced tumor cell proliferation and stemness, regulated tumor immunity and metabolism, and improved response to chemotherapy. Intriguingly, tumor RANK protein expression associated with poor prognosis in postmenopausal breast cancer patients, activation of NFKB signaling, and modulation of immune and metabolic pathways, suggesting that RANK signaling increases after menopause. Our results demonstrate that RANK protein expression is an independent biomarker of poor prognosis in postmenopausal and ER− breast cancer patients and support the therapeutic benefit of RANK pathway inhibitors, such as denosumab, in breast cancer patients with RANK+ ER− tumors after menopause. |
| first_indexed | 2024-03-07T16:39:05Z |
| format | Article |
| id | doaj.art-1a7e932a6a184ce6a384d4a58e43a0be |
| institution | Directory Open Access Journal |
| issn | 1757-4676 1757-4684 |
| language | English |
| last_indexed | 2024-03-07T16:39:05Z |
| publishDate | 2023-04-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj.art-1a7e932a6a184ce6a384d4a58e43a0be2024-03-03T08:59:08ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842023-04-01154n/an/a10.15252/emmm.202216715RANK is a poor prognosis marker and a therapeutic target in ER‐negative postmenopausal breast cancerMarina Ciscar0Eva M Trinidad1Gema Perez‐Chacon2Mansour Alsaleem3Maria Jimenez4Maria J Jimenez‐Santos5Hector Perez‐Montoyo6Adrian Sanz‐Moreno7Andrea Vethencourt8Michael Toss9Anna Petit10Maria T Soler‐Monso11Victor Lopez12Jorge Gomez‐Miragaya13Clara Gomez‐Aleza14Lacey E Dobrolecki15Michael T Lewis16Alejandra Bruna17Silvana Mouron18Miguel Quintela‐Fandino19Fatima Al‐Shahrour20Antonio Martinez‐Aranda21Angels Sierra22Andrew R Green23Emad Rakha24Eva Gonzalez‐Suarez25Molecular Oncology, Spanish National Cancer Research Centre (CNIO) Madrid SpainOncobell, Bellvitge Biomedical Research Institute (IDIBELL) Barcelona SpainMolecular Oncology, Spanish National Cancer Research Centre (CNIO) Madrid SpainNottingham Breast Cancer Research Centre, Academic Unit for Translational Medical Sciences, School of Medicine University of Nottingham Biodiscovery Institute, University Park Nottingham UKMolecular Oncology, Spanish National Cancer Research Centre (CNIO) Madrid SpainBioinformatics Unit, Structural Biology, Spanish National Cancer Research Centre (CNIO) Madrid SpainOncobell, Bellvitge Biomedical Research Institute (IDIBELL) Barcelona SpainOncobell, Bellvitge Biomedical Research Institute (IDIBELL) Barcelona SpainOncobell, Bellvitge Biomedical Research Institute (IDIBELL) Barcelona SpainNottingham Breast Cancer Research Centre, Academic Unit for Translational Medical Sciences, School of Medicine University of Nottingham Biodiscovery Institute, University Park Nottingham UKPathology Department University Hospital of Bellvitge, IDIBELL Barcelona SpainPathology Department University Hospital of Bellvitge, IDIBELL Barcelona SpainMolecular Oncology, Spanish National Cancer Research Centre (CNIO) Madrid SpainOncobell, Bellvitge Biomedical Research Institute (IDIBELL) Barcelona SpainOncobell, Bellvitge Biomedical Research Institute (IDIBELL) Barcelona SpainMolecular and Cellular Biology and Radiology The Lester and Sue Smith Breast Center, Baylor College of Medicine Houston Texas USAMolecular and Cellular Biology and Radiology The Lester and Sue Smith Breast Center, Baylor College of Medicine Houston Texas USACancer Research UK Cambridge Centre Cambridge UKBreast Cancer Clinical Research Unit, Clinical Research Program Spanish National Cancer Research Centre (CNIO) Madrid SpainBreast Cancer Clinical Research Unit, Clinical Research Program Spanish National Cancer Research Centre (CNIO) Madrid SpainBioinformatics Unit, Structural Biology, Spanish National Cancer Research Centre (CNIO) Madrid SpainOncobell, Bellvitge Biomedical Research Institute (IDIBELL) Barcelona SpainOncobell, Bellvitge Biomedical Research Institute (IDIBELL) Barcelona SpainNottingham Breast Cancer Research Centre, Academic Unit for Translational Medical Sciences, School of Medicine University of Nottingham Biodiscovery Institute, University Park Nottingham UKNottingham Breast Cancer Research Centre, Academic Unit for Translational Medical Sciences, School of Medicine University of Nottingham Biodiscovery Institute, University Park Nottingham UKMolecular Oncology, Spanish National Cancer Research Centre (CNIO) Madrid SpainAbstract Despite strong preclinical data, the therapeutic benefit of the RANKL inhibitor, denosumab, in breast cancer patients, beyond the bone, is unclear. Aiming to select patients who may benefit from denosumab, we hereby analyzed RANK and RANKL protein expression in more than 2,000 breast tumors (777 estrogen receptor‐negative, ER−) from four independent cohorts. RANK protein expression was more frequent in ER− tumors, where it associated with poor outcome and poor response to chemotherapy. In ER− breast cancer patient‐derived orthoxenografts (PDXs), RANKL inhibition reduced tumor cell proliferation and stemness, regulated tumor immunity and metabolism, and improved response to chemotherapy. Intriguingly, tumor RANK protein expression associated with poor prognosis in postmenopausal breast cancer patients, activation of NFKB signaling, and modulation of immune and metabolic pathways, suggesting that RANK signaling increases after menopause. Our results demonstrate that RANK protein expression is an independent biomarker of poor prognosis in postmenopausal and ER− breast cancer patients and support the therapeutic benefit of RANK pathway inhibitors, such as denosumab, in breast cancer patients with RANK+ ER− tumors after menopause.https://doi.org/10.15252/emmm.202216715breast cancer patient‐derived xenograftsER negative breast cancermenopausepharmacological RANKL inhibitorsRANK‐RANKL |
| spellingShingle | Marina Ciscar Eva M Trinidad Gema Perez‐Chacon Mansour Alsaleem Maria Jimenez Maria J Jimenez‐Santos Hector Perez‐Montoyo Adrian Sanz‐Moreno Andrea Vethencourt Michael Toss Anna Petit Maria T Soler‐Monso Victor Lopez Jorge Gomez‐Miragaya Clara Gomez‐Aleza Lacey E Dobrolecki Michael T Lewis Alejandra Bruna Silvana Mouron Miguel Quintela‐Fandino Fatima Al‐Shahrour Antonio Martinez‐Aranda Angels Sierra Andrew R Green Emad Rakha Eva Gonzalez‐Suarez RANK is a poor prognosis marker and a therapeutic target in ER‐negative postmenopausal breast cancer EMBO Molecular Medicine breast cancer patient‐derived xenografts ER negative breast cancer menopause pharmacological RANKL inhibitors RANK‐RANKL |
| title | RANK is a poor prognosis marker and a therapeutic target in ER‐negative postmenopausal breast cancer |
| title_full | RANK is a poor prognosis marker and a therapeutic target in ER‐negative postmenopausal breast cancer |
| title_fullStr | RANK is a poor prognosis marker and a therapeutic target in ER‐negative postmenopausal breast cancer |
| title_full_unstemmed | RANK is a poor prognosis marker and a therapeutic target in ER‐negative postmenopausal breast cancer |
| title_short | RANK is a poor prognosis marker and a therapeutic target in ER‐negative postmenopausal breast cancer |
| title_sort | rank is a poor prognosis marker and a therapeutic target in er negative postmenopausal breast cancer |
| topic | breast cancer patient‐derived xenografts ER negative breast cancer menopause pharmacological RANKL inhibitors RANK‐RANKL |
| url | https://doi.org/10.15252/emmm.202216715 |
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