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4. RANK is a poor prognosis marker and a therapeutic target in ER‐negative postmenopausal breast cancer

Author

Ciscar, Marina, Trinidad, Eva M, Perez‐Chacon, Gema, Alsaleem, Mansour, Jimenez, Maria, Jimenez‐Santos, Maria J, Perez‐Montoyo, Hector, Sanz‐Moreno, Adrian, Vethencourt, Andrea, Toss, Michael, Petit, Anna, Soler‐Monso, Maria T, Lopez, Victor, Gomez‐Miragaya, Jorge, Gomez‐Aleza, Clara, Dobrolecki, Lacey E, Lewis, Michael T, Bruna, Alejandra, Mouron, Silvana, Quintela‐Fandino, Miguel, Al‐Shahrour, Fatima, Martinez‐Aranda, Antonio, Sierra, Angels, Green, Andrew R, Rakha, Emad, and Gonzalez‐Suarez, Eva

Published
2023
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5. A clinically compatible drug‐screening platform based on organotypic cultures identifies vulnerabilities to prevent and treat brain metastasis

Author

Zhu, Lucía, Retana, Diana, García‐Gómez, Pedro, Álvaro‐Espinosa, Laura, Priego, Neibla, Masmudi‐Martín, Mariam, Yebra, Natalia, Miarka, Lauritz, Hernández‐Encinas, Elena, Blanco‐Aparicio, Carmen, Martínez, Sonia, Sobrino, Cecilia, Ajenjo, Nuria, Artiga, Maria‐Jesus, Ortega‐Paino, Eva, Torres‐Ruiz, Raúl, Rodríguez‐Perales, Sandra, Soffietti, Riccardo, Bertero, Luca, Cassoni, Paola, Weiss, Tobias, Muñoz, Javier, Sepúlveda, Juan Manuel, González‐León, Pedro, Jiménez‐Roldán, Luis, Moreno, Luis Miguel, Esteban, Olga, Pérez‐Núñez, Ángel, Hernández‐Laín, Aurelio, Toldos, Oscar, Ruano, Yolanda, Alcázar, Lucía, Blasco, Guillermo, Fernández‐Alén, José, Caleiras, Eduardo, Lafarga, Miguel, Megías, Diego, Graña‐Castro, Osvaldo, Nör, Carolina, Taylor, Michael D, Young, Leonie S, Varešlija, Damir, Cosgrove, Nicola, Couch, Fergus J, Cussó, Lorena, Desco, Manuel, Mouron, Silvana, Quintela‐Fandino, Miguel, Weller, Michael, Pastor, Joaquín, Valiente, Manuel, de la Lama‐Zaragoza, Adolfo, Calero‐Felix, Lourdes, Fiaño‐Valverde, Concepcion, Delgado‐López, Pedro David, Montalvo‐Afonso, Antonio, Pascual‐Llorente, Mar, Díaz‐Piqueras, Ángela, Nam‐Cha, SH, Barrena López, Cristina, Plans Ahicart, Gerard, Martínez‐Saez, Elena, Ramón y Cajal, Santiago, and Nicolás, Pilar

Published
2022
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9. Immuno-priming durvalumab with bevacizumab in HER2-negative advanced breast cancer: a pilot clinical trial

Author

Quintela-Fandino, Miguel, Holgado, Esther, Manso, Luis, Morales, Serafin, Bermejo, Begoña, Colomer, Ramon, Apala, Juan V., Blanco, Raquel, Muñoz, Manuel, Caleiras, Eduardo, Iranzo, Vega, Martinez, Mario, Dominguez, Orlando, Hornedo, Javier, Gonzalez-Cortijo, Lucia, Cortes, Javier, Gasol Cudos, Ariadna, Malon, Diego, Lopez-Alonso, Antonio, Moreno-Ortíz, María C., Mouron, Silvana, and Mañes, Santos

Published
2020
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10. RANK is a poor prognosis marker and a therapeutic target in ER‐negative postmenopausal breast cancer

Author

Ministerio de Economía y Competitividad (España), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Instituto de Salud Carlos III, European Commission, Susan G. Komen Foundation, Generalitat de Catalunya, European Research Council, Amgen, Ministerio de Sanidad y Consumo (España), National Institutes of Health (US), Cancer Prevention and Research Institute of Texas, Ciscar, Marina, Trinidad, Eva M., Pérez-Chacón, Gema, Alsaleem, Mansour, Jiménez, María, Jiménez-Santos, María J., Pérez-Montoyo, Héctor, Sanz-Moreno, Adrián, Vethencourt, Andrea, Toss, Michael, Petit, Anna, Soler-Monso, María T., López, Victor, Gómez-Miragaya, Jorge, Gómez-Aleza, Clara, Dobrolecki, Lacey E., Lewis, Michael T., Bruna, Alejandra, Mouron, Silvana, Quintela-Fandino, Miguel, Al-Shahrour, Fátima, Martínez-Aranda, Antonio, Sierra, Angels, Green, Andrew R., Rakha, Emad, González-Suarez, Eva, Ministerio de Economía y Competitividad (España), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Instituto de Salud Carlos III, European Commission, Susan G. Komen Foundation, Generalitat de Catalunya, European Research Council, Amgen, Ministerio de Sanidad y Consumo (España), National Institutes of Health (US), Cancer Prevention and Research Institute of Texas, Ciscar, Marina, Trinidad, Eva M., Pérez-Chacón, Gema, Alsaleem, Mansour, Jiménez, María, Jiménez-Santos, María J., Pérez-Montoyo, Héctor, Sanz-Moreno, Adrián, Vethencourt, Andrea, Toss, Michael, Petit, Anna, Soler-Monso, María T., López, Victor, Gómez-Miragaya, Jorge, Gómez-Aleza, Clara, Dobrolecki, Lacey E., Lewis, Michael T., Bruna, Alejandra, Mouron, Silvana, Quintela-Fandino, Miguel, Al-Shahrour, Fátima, Martínez-Aranda, Antonio, Sierra, Angels, Green, Andrew R., Rakha, Emad, and González-Suarez, Eva

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.

Published
2023

14. Figure S2 from Randomized Phase 0/I Trial of the Mitochondrial Inhibitor ME-344 or Placebo Added to Bevacizumab in Early HER2-Negative Breast Cancer

Author

Quintela-Fandino, Miguel, primary, Morales, Serafín, primary, Cortés-Salgado, Alfonso, primary, Manso, Luis, primary, Apala, Juan V., primary, Muñoz, Manuel, primary, Gasol Cudos, Ariadna, primary, Salla Fortuny, Joel, primary, Gion, María, primary, Lopez-Alonso, Antonio, primary, Cortés, Javier, primary, Guerra, Juan, primary, Malón, Diego, primary, Caleiras, Eduardo, primary, Mulero, Francisca, primary, and Mouron, Silvana, primary

Published
2023
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15. Abstract P5-02-28: p27Kip1 V109G single-nucleotide polymorphism (SNP): pinpointing the hormone-receptor positive breast cancer subpopulation that requires CDK4/6 inhibitors in addition to endocrine therapy

Author

Quintela-Fandino, Miguel, primary, Mouron, Silvana, additional, Bueno, Maria J., additional, Muñoz, Manuel, additional, Torres, Raul, additional, Rodriguez, Sandra, additional, Sánchez-Bayona, Rodrigo, additional, Manso, Luis, additional, Silva, Jorge, additional, and Malumbres, Marcos, additional

Published
2023
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16. p27Kip1 V109G as a biomarker for CDK4/6 inhibitors indication in hormone receptor-positive breast cancer

Author

Mouron, Silvana, primary, Bueno, Maria J, additional, Muñoz, Manuel, additional, Torres, Raul, additional, Rodríguez, Sandra, additional, Apala, Juan V, additional, Silva, Jorge, additional, Sánchez-Bayona, Rodrigo, additional, Manso, Luis, additional, Guerra, Juan, additional, Rodriguez-Lajusticia, Laura, additional, Malon, Diego, additional, Malumbres, Marcos, additional, and Quintela-Fandino, Miguel, additional

Published
2023
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17. Tumor P70S6K hyperactivation is inversely associated with tumor-infiltrating lymphocytes in triple-negative breast cancer

Author

Jimeno, Rebeca, primary, Mouron, Silvana, additional, Salgado, Roberto, additional, Loi, Sherene, additional, Pérez-Mies, Belén, additional, Sánchez-Bayona, Rodrigo, additional, Manso, Luis, additional, Martínez, Mario, additional, Garrido-García, Ana, additional, Serrano-Pardo, Rosario, additional, Colomer, Ramón, additional, and Quintela-Fandino, Miguel, additional

Published
2022
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20. Abstract OT2-19-08: Phase IB/II trial of palbociclib and binimetinib in advanced triple-negative breast cancer with hyperactivation of ERK and/or CDK4/6

Author

Manso, Luis, primary, Cortes, Alfonso, additional, Cejalvo, Juan M, additional, Morales, Serafin, additional, Saenz, Jose A García, additional, Colomer, Ramon, additional, Sanchez-Bayona, Rodrigo, additional, Silva, Jorge, additional, Guerra, Juan A, additional, Malon, Diego, additional, Mouron, Silvana, additional, Caleiras, Eduardo, additional, and Quintela-Fandino, Miguel, additional

Published
2022
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21. Abstract OT2-20-01: Rogaratinib, palbociclib and fulvestrant in advanced hormone receptor-positive (HR+), FGFR1/2-positive breast cancer: Phase I trial plus an expansion cohort

Author

Pernas, Sonia, primary, Hernando, Cristina, additional, Bermejo, Begoña, additional, Martinez-Jañez, Noelia, additional, Saenz, Jose A García, additional, Morales, Serafin, additional, Manso, Luis, additional, Silva, Jorge, additional, Guerra, Juan A, additional, Malon, Diego, additional, Mouron, Silvana, additional, Caleiras, Eduardo, additional, and Quintela-Fandino, Miguel, additional

Published
2022
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22. RANK is an independent biomarker of poor prognosis in estrogen receptor-negative breast cancer and a therapeutic target in patient-derived xenografts

Author

Ciscar, Marina, primary, Trinidad, Eva M, additional, Perez-Montoyo, Hector, additional, Alsaleem, Mansour, additional, Jimenez-Santos, Maria J, additional, Toss, Michael, additional, Sanz-Moreno, Adrian, additional, Vethencourt, Andrea, additional, Perez-Chacon, Gema, additional, Petit, Anna, additional, Soler-Monso, Maria T, additional, Gomez-Miragaya, Jorge, additional, Gomez-Aleza, Clara, additional, Jimenez, Maria, additional, Dobrolecki, Lacey E, additional, Lewis, Michael T, additional, Bruna, Alejandra, additional, Mouron, Silvana, additional, Quintela-Fandino, Miguel, additional, Alshahrour, Fatima, additional, Martinez-Aranda, Antonio, additional, Sierra, Angels, additional, Green, Andrew R, additional, Rakha, Emad, additional, and Gonzalez-Suarez, Eva, additional

Published
2021
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23. Prolonged estrogen deprivation triggers a broad immunosuppressive phenotype in breast cancer cells

Author

Hühn, Daniela, primary, Martí‐Rodrigo, Pablo, additional, Mouron, Silvana, additional, Hansel, Catherine, additional, Tschapalda, Kirsten, additional, Porebski, Bartlomiej, additional, Häggblad, Maria, additional, Lidemalm, Louise, additional, Quintela‐Fandino, Miguel, additional, Carreras‐Puigvert, Jordi, additional, and Fernandez‐Capetillo, Oscar, additional

Published
2021
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32. Prolonged estrogen deprivation triggers a broad immunosuppressive phenotype in breast cancer cells

Author

Hühn, Daniela, Martí‐Rodrigo, Pablo, Mouron, Silvana, Hansel, Catherine, Tschapalda, Kirsten, Porebski, Bartlomiej, Häggblad, Maria, Lidemalm, Louise, Quintela‐Fandino, Miguel, Carreras-Puigvert, Jordi, Fernandez‐Capetillo, Oscar, Hühn, Daniela, Martí‐Rodrigo, Pablo, Mouron, Silvana, Hansel, Catherine, Tschapalda, Kirsten, Porebski, Bartlomiej, Häggblad, Maria, Lidemalm, Louise, Quintela‐Fandino, Miguel, Carreras-Puigvert, Jordi, and Fernandez‐Capetillo, Oscar

Abstract

Among others, expression levels of programmed cell death 1 ligand 1 (PD-L1) have been explored as biomarkers of the response to immune checkpoint inhibitors in cancer therapy. Here, we present the results of a chemical screen that interrogated how medically approved drugs influence PD-L1 expression. As expected, corticosteroids and inhibitors of Janus kinases were among the top PD-L1 downregulators. In addition, we identified that PD-L1 expression is induced by antiestrogenic compounds. Transcriptomic analyses indicate that chronic estrogen receptor alpha (ER alpha) inhibition triggers a broad immunosuppressive program in ER-positive breast cancer cells, which is subsequent to their growth arrest and involves the activation of multiple immune checkpoints together with the silencing of the antigen-presenting machinery. Accordingly, estrogen-deprived MCF7 cells are resistant to T-cell-mediated cell killing, in a manner that is independent of PD-L1, but which is reverted by estradiol. Our study reveals that while antiestrogen therapies efficiently limit the growth of ER-positive breast cancer cells, they concomitantly trigger a transcriptional program that favors their immune evasion., De 2 sista författarna delar sistaförfattarskapet.

Published
2021
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33. RANK is an independent biomarker of poor prognosis in estrogen receptor-negative breast cancer and a therapeutic target in patient-derived xenografts

Author

Ciscar, Marina, Trinidad, Eva M., Pérez-Montoyo, Héctor, Alsaleem, Mansour, Jiménez-Santos, María J., Toss, Michael, Sanz-Moreno, Adrián, Vethencourt, Andrea, Pérez-Chacón, Gema, Petit, Anna, Soler-Monso, María T., Gómez-Miragaya, Jorge, Gómez-Aleza, Clara, Jiménez, María, Dobrolecki, Lacey E., Lewis, Michael T., Bruna, Alejandra, Mouron, Silvana, Quintela-Fandino, Miguel, Al-Shahrour, Fátima, Martínez-Aranda, Antonio, Sierra, Angels, Green, Andrew R., Rakha, Emad, González-Suarez, Eva, Ciscar, Marina, Trinidad, Eva M., Pérez-Montoyo, Héctor, Alsaleem, Mansour, Jiménez-Santos, María J., Toss, Michael, Sanz-Moreno, Adrián, Vethencourt, Andrea, Pérez-Chacón, Gema, Petit, Anna, Soler-Monso, María T., Gómez-Miragaya, Jorge, Gómez-Aleza, Clara, Jiménez, María, Dobrolecki, Lacey E., Lewis, Michael T., Bruna, Alejandra, Mouron, Silvana, Quintela-Fandino, Miguel, Al-Shahrour, Fátima, Martínez-Aranda, Antonio, Sierra, Angels, Green, Andrew R., Rakha, Emad, and González-Suarez, Eva

Abstract

Despite strong preclinical data, the therapeutic benefit of the RANKL inhibitor denosumab in BC patients, beyond its bone-related effects, is unclear. Here, we investigated the prognostic value of RANK expression and its functionality in human BC. We analyzed RANK and RANKL expression in more than 1500 BC cases (777 being estrogen receptor-negative (ER-)) from four independent cohorts. We confirmed that RANK is more frequently expressed in ER- tumors, but it is also found in a subset of ER+ tumors. In ER- BC, RANK expression was independently associated with poor outcome, especially in postmenopausal patients and those who received adjuvant chemotherapy. Gene expression analyses unraveled distinct biology associated with RANK in relation to ER expression and menopause, and evidenced enhanced RANK activation in ER- postmenopausal tumors, together with regulation of metabolic pathways. Functional studies and transcriptomic analyses in ER- RANK+ patients-derived orthoxenografts demonstrated that activation of RANK signaling pathway promotes tumor cell proliferation and stemness, and regulates multiple biological processes including tumor immune surveillance and metabolism. Our results demonstrate that RANK expression is an independent poor prognosis biomarker in postmenopausal ER- BC patients and support the rational of using RANK pathway inhibitors in combination with chemotherapy in ER- BC.

Published
2021

35. Additional file 2 of Immuno-priming durvalumab with bevacizumab in HER2-negative advanced breast cancer: a pilot clinical trial

Author

Quintela-Fandino, Miguel, Holgado, Esther, Manso, Luis, Morales, Serafin, Bermejo, Begoña, Colomer, Ramon, Apala, Juan V., Blanco, Raquel, Muñoz, Manuel, Caleiras, Eduardo, Iranzo, Vega, Martinez, Mario, Dominguez, Orlando, Hornedo, Javier, Gonzalez-Cortijo, Lucia, Cortes, Javier, Cudos, Ariadna Gasol, Malon, Diego, Lopez-Alonso, Antonio, Moreno-Ortíz, María C., Mouron, Silvana, and Mañes, Santos

Subjects
hemic and immune systems, chemical and pharmacologic phenomena
Abstract

Additional file 2 : Supplementary Figure S2: Flow cytometry gating strategy for Treg cells. Representative gating strategy used in Treg cell immunophenotyping based on the exclusion of dead cells, the selection of the lymphoid cells by size and complexity, and then the surface expression of CD3, CD4, CD25, CD127, CCR4, HLA-DR and CD45RO markers. After the initial selection of CD4+ T cells (CD3+CD4+), Treg cells were identified as CD25+CD127low double positive cells. The combination of CCR4 and CD45RO markers allowed the identification of naïve Treg (CCR4+,CD45RO−) and memory Treg (CCR4+CD45RO+), whereas HLA-DR positivity identified activated cells in these Treg subpopulations.

Published
2020
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36. Additional file 6 of Immuno-priming durvalumab with bevacizumab in HER2-negative advanced breast cancer: a pilot clinical trial

Author

Quintela-Fandino, Miguel, Holgado, Esther, Manso, Luis, Morales, Serafin, Bermejo, Begoña, Colomer, Ramon, Apala, Juan V., Blanco, Raquel, Muñoz, Manuel, Caleiras, Eduardo, Iranzo, Vega, Martinez, Mario, Dominguez, Orlando, Hornedo, Javier, Gonzalez-Cortijo, Lucia, Cortes, Javier, Cudos, Ariadna Gasol, Malon, Diego, Lopez-Alonso, Antonio, Moreno-Ortíz, María C., Mouron, Silvana, and Mañes, Santos

Abstract

Additional file 6 : Supplementary Table 1: Antibodies used for immunophenotyping in peripheral blood.

Published
2020
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37. Additional file 4 of Immuno-priming durvalumab with bevacizumab in HER2-negative advanced breast cancer: a pilot clinical trial

Author

Quintela-Fandino, Miguel, Holgado, Esther, Manso, Luis, Morales, Serafin, Bermejo, Begoña, Colomer, Ramon, Apala, Juan V., Blanco, Raquel, Muñoz, Manuel, Caleiras, Eduardo, Iranzo, Vega, Martinez, Mario, Dominguez, Orlando, Hornedo, Javier, Gonzalez-Cortijo, Lucia, Cortes, Javier, Cudos, Ariadna Gasol, Malon, Diego, Lopez-Alonso, Antonio, Moreno-Ortíz, María C., Mouron, Silvana, and Mañes, Santos

Abstract

Additional file 4 : Supplementary Figure 4: Immunophenotyping of leukocyte populations in the baseline sample of responders and non-responder patients. (A-D) Analysis of the indicated leukocyte subtypes in the baseline blood sample of the patients stratified according to their clinical response. The percentages of the main leukocyte subtypes (A), CD4+ and CD8+ T cells (B), monocyte subtypes (C) and DC subtypes (D) are shown.

Published
2020
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38. Additional file 3 of Immuno-priming durvalumab with bevacizumab in HER2-negative advanced breast cancer: a pilot clinical trial

Author

Quintela-Fandino, Miguel, Holgado, Esther, Manso, Luis, Morales, Serafin, Bermejo, Begoña, Colomer, Ramon, Apala, Juan V., Blanco, Raquel, Muñoz, Manuel, Caleiras, Eduardo, Iranzo, Vega, Martinez, Mario, Dominguez, Orlando, Hornedo, Javier, Gonzalez-Cortijo, Lucia, Cortes, Javier, Cudos, Ariadna Gasol, Malon, Diego, Lopez-Alonso, Antonio, Moreno-Ortíz, María C., Mouron, Silvana, and Mañes, Santos

Subjects
immune system diseases, chemical and pharmacologic phenomena, hemic and immune systems
Abstract

Additional file 3 : Supplementary Figure S3: Flow cytometry gating strategy for innate cell populations. Representative example of the gating strategy used for immunophenotyping of the indicated innate subpopulations. After the exclusion of dead cells, monocytes were selected by size and complexity; subtypes were identified by CD14 and CD16 staining, allowing the identification of classical monocytes (CD14+ CD16−), alternative monocytes (CD14−CD16+) and intermediate monocytes. For DC and NK, leukocytes were selected by size and complexity in the live cells, and T- and B-lymphocytes excluded by staining with lineage-specific antibodies. Dendritic cells (DC) and NK cells were selected within the CD20− and CD14− population; NK cells were identified as CD56+ cells (both CD16+ and CD16−) and DC as HLA-DR+CD16− cells. DC subtypes were further defined by CD11c+ (myeloid DC) or CD123+ (plasmacytoid DC).

Published
2020
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39. Additional file 1 of Immuno-priming durvalumab with bevacizumab in HER2-negative advanced breast cancer: a pilot clinical trial

Author

Quintela-Fandino, Miguel, Holgado, Esther, Manso, Luis, Morales, Serafin, Bermejo, Begoña, Colomer, Ramon, Apala, Juan V., Blanco, Raquel, Muñoz, Manuel, Caleiras, Eduardo, Iranzo, Vega, Martinez, Mario, Dominguez, Orlando, Hornedo, Javier, Gonzalez-Cortijo, Lucia, Cortes, Javier, Cudos, Ariadna Gasol, Malon, Diego, Lopez-Alonso, Antonio, Moreno-Ortíz, María C., Mouron, Silvana, and Mañes, Santos

Subjects
immune system diseases, virus diseases, chemical and pharmacologic phenomena, hemic and immune systems, circulatory and respiratory physiology
Abstract

Additional file 1 : Supplementary Figure S1: Flow cytometry gating strategy for T cells. Representative gating strategy used in T cell immunophenotyping based on the exclusion of dead cells, the selection of the lymphoid cells by size and complexity, and then the surface expression of CD3, CD4, CD8, CCR7 and CD45RA. The combination of these markers allowed the identification of naïve cells (CCR7+CD45RA+), Teff (CCR7−,CD45RA+), TCM (CCR7+CD45RA−), and TEM (CCR7−CD45RA−). Staining with the CD38 marker allowed the identification of activated cells, which were minimally detected only in Teff and TEM subpopulations.

Published
2020
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42. Lafora bodies and neurological defects in malin-deficient mice correlate with impaired autophagy

Author

Criado, Olga, Aguado, Carmen, Gayarre, Javier, Duran-Trio, Lara, Garcia-Cabrero, Ana M., Vernia, Santiago, San Millán, Beatriz, Heredia, Miguel, Romá-Mateo, Carlos, Mouron, Silvana, Juana-López, Lucía, Domínguez, Mercedes, Navarro, Carmen, Serratosa, Jose M., Sanchez, Marina, Sanz, Pascual, Bovolenta, Paola, Knecht, Erwin, and Rodriguez de Cordoba, Santiago

Published
2012
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44. Randomized Phase 0/I Trial of the Mitochondrial Inhibitor ME-344 or Placebo Added to Bevacizumab in Early HER2-Negative Breast Cancer

Author

Quintela-Fandino, Miguel, primary, Morales, Serafín, additional, Cortés-Salgado, Alfonso, additional, Manso, Luis, additional, Apala, Juan V., additional, Muñoz, Manuel, additional, Gasol Cudos, Ariadna, additional, Salla Fortuny, Joel, additional, Gion, María, additional, Lopez-Alonso, Antonio, additional, Cortés, Javier, additional, Guerra, Juan, additional, Malón, Diego, additional, Caleiras, Eduardo, additional, Mulero, Francisca, additional, and Mouron, Silvana, additional

Published
2020
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47. Prolonged estrogen deprivation triggers a broad immunosuppressive phenotype in breast cancer cells.

Author

Hühn, Daniela, Martí‐Rodrigo, Pablo, Mouron, Silvana, Hansel, Catherine, Tschapalda, Kirsten, Porebski, Bartlomiej, Häggblad, Maria, Lidemalm, Louise, Quintela‐Fandino, Miguel, Carreras‐Puigvert, Jordi, and Fernandez‐Capetillo, Oscar

Abstract

Among others, expression levels of programmed cell death 1 ligand 1 (PD‐L1) have been explored as biomarkers of the response to immune checkpoint inhibitors in cancer therapy. Here, we present the results of a chemical screen that interrogated how medically approved drugs influence PD‐L1 expression. As expected, corticosteroids and inhibitors of Janus kinases were among the top PD‐L1 downregulators. In addition, we identified that PD‐L1 expression is induced by antiestrogenic compounds. Transcriptomic analyses indicate that chronic estrogen receptor alpha (ERα) inhibition triggers a broad immunosuppressive program in ER‐positive breast cancer cells, which is subsequent to their growth arrest and involves the activation of multiple immune checkpoints together with the silencing of the antigen‐presenting machinery. Accordingly, estrogen‐deprived MCF7 cells are resistant to T‐cell‐mediated cell killing, in a manner that is independent of PD‐L1, but which is reverted by estradiol. Our study reveals that while antiestrogen therapies efficiently limit the growth of ER‐positive breast cancer cells, they concomitantly trigger a transcriptional program that favors their immune evasion. [ABSTRACT FROM AUTHOR]

Published
2022
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49. In vivo phosphoproteomics reveals kinase activity profiles that predict treatment outcome in triple-negative breast cancer

Author

Zagorac, Ivana, Fernandez-Gaitero, Sara, Penning, Renske, Post, Harm, Bueno, Maria J, Mouron, Silvana, Manso, Luis, Morente, Manuel M, Alonso, Soledad, Serra, Violeta, Muñoz, Javier, Gómez-López, Gonzalo, Lopez-Acosta, Jose Francisco, Jimenez-Renard, Veronica, Gris-Oliver, Albert, Al-Shahrour, Fatima, Piñeiro-Yañez, Elena, Montoya-Suarez, Jose Luis, Apala, Juan V, Moreno-Torres, Amalia, Colomer, Ramon, Dopazo, Ana, Heck, Albert J R, Altelaar, Maarten, Quintela-Fandino, Miguel, Afd Biomol.Mass Spect. and Proteomics, Sub Biomol.Mass Spectrometry & Proteom., Biomolecular Mass Spectrometry and Proteomics, Unión Europea. Comisión Europea, Netherlands Organisation for Scientific Research, CRIS Cancer Foundation (UK), Asociación Española Contra el Cáncer, Fundación La Caixa, Instituto de Salud Carlos III, Afd Biomol.Mass Spect. and Proteomics, Sub Biomol.Mass Spectrometry & Proteom., and Biomolecular Mass Spectrometry and Proteomics

Subjects
0301 basic medicine, Gerontology, EXPRESSION, Science, INHIBITION, General Physics and Astronomy, PEPTIDE IDENTIFICATION, Triple Negative Breast Neoplasms, Kaplan-Meier Estimate, General Biochemistry, Genetics and Molecular Biology, Article, Mass Spectrometry, THERAPEUTIC TARGETS, 03 medical and health sciences, Text mining, Breast cancer, Downregulation and upregulation, Cell Line, Tumor, medicine, Humans, Kinase activity, lcsh:Science, Triple-negative breast cancer, Multidisciplinary, LANDSCAPE, business.industry, Kinase, TUMOR XENOGRAFTS, SET ENRICHMENT ANALYSIS, Phosphotransferases, Phosphoproteomics, General Chemistry, SOMATIC MUTATIONS, medicine.disease, Phosphoproteins, Immunohistochemistry, 3. Good health, C-KIT, 030104 developmental biology, Treatment Outcome, Cancer research, lcsh:Q, Female, business
Abstract

Triple-negative breast cancer (TNBC) lacks prognostic and predictive markers. Here, we use high-throughput phosphoproteomics to build a functional TNBC taxonomy. A cluster of 159 phosphosites is upregulated in relapsed cases of a training set (n = 34 patients), with 11 hyperactive kinases accounting for this phosphoprofile. A mass-spectrometry-to-immunohistochemistry translation step, assessing 2 independent validation sets, reveals 6 kinases with preserved independent prognostic value. The kinases split the validation set into two patterns: one without hyperactive kinases being associated with a >90% relapse-free rate, and the other one showing ≥1 hyperactive kinase and being associated with an up to 9.5-fold higher relapse risk. Each kinase pattern encompasses different mutational patterns, simplifying mutation-based taxonomy. Drug regimens designed based on these 6 kinases show promising antitumour activity in TNBC cell lines and patient-derived xenografts. In summary, the present study elucidates phosphosites and kinases implicated in TNBC and suggests a target-based clinical classification system for TNBC., Triple-negative breast cancer (TNBC) lacks prognostic and predictive markers. Here, the authors use phosphoproteomics to define kinases with distinct activity profiles in TNBC, demonstrating their prognostic value as well as their utility for simplifying TNBC classification and designing drug regimens.

Published
2018

50. Estrogen deprivation triggers an immunosuppressive phenotype in breast cancer cells

Author

Hühn, Daniela, primary, Martí-Rodrigo, Pablo, additional, Mouron, Silvana, additional, Hansel, Catherine S., additional, Tschapalda, Kirsten, additional, Porebski, Bartlomiej, additional, Häggblad, Maria, additional, Lidemalm, Louise, additional, Quintela-Fandino, Miguel A., additional, Carreras-Puigvert, Jordi, additional, and Fernandez-Capetillo, Oscar, additional

Published
2019
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