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1. Blockade of Stat3 oncogene addiction induces cellular senescence and reveals a cell-nonautonomous activity suitable for cancer immunotherapy

Author

Mara De Martino, Mercedes Tkach, Sofía Bruni, Darío Rocha, María F. Mercogliano, Mauro E. Cenciarini, María F. Chervo, Cecilia J. Proietti, Florent Dingli, Damarys Loew, Elmer A. Fernández, Patricia V. Elizalde, Eliane Piaggio, and Roxana Schillaci

Subjects
stat3, immunotherapy, senescence, oncogene addiction, immune checkpoint blockade, Immunologic diseases. Allergy, RC581-607, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Stat3 is constitutively activated in several tumor types and plays an essential role in maintaining their malignant phenotype and immunosupression. To take advantage of the promising antitumor activity of Stat3 targeting, it is vital to understand the mechanism by which Stat3 regulates both cell autonomous and non-autonomous processes. Here, we demonstrated that turning off Stat3 constitutive activation in different cancer cell types induces senescence, thus revealing their Stat3 addiction. Taking advantage of the senescence-associated secretory phenotype (SASP) induced by Stat3 silencing (SASP-siStat3), we designed an immunotherapy. The administration of SASP-siStat3 immunotherapy induced a strong inhibition of triple-negative breast cancer and melanoma growth associated with activation of CD4 + T and NK cells. Combining this immunotherapy with anti-PD-1 antibody resulted in survival improvement in mice bearing melanoma. The characterization of the SASP components revealed that type I IFN-related mediators, triggered by the activation of the cyclic GMP-AMP synthase DNA sensing pathway, are important for its immunosurveillance activity. Overall, our findings provided evidence that administration of SASP-siStat3 or low dose of Stat3-blocking agents would benefit patients with Stat3-addicted tumors to unleash an antitumor immune response and to improve the effectiveness of immune checkpoint inhibitors.

Published
2020
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2. Figure S1-S8 from Tamoxifen Resistance in Breast Cancer Is Regulated by the EZH2–ERα–GREB1 Transcriptional Axis

Author

Kexin Xu, Myles Brown, Rachel Schiff, Patricia V. Elizalde, Xiaoyong Fu, Carmine De Angelis, Rong Li, Tim Hui-Ming Huang, Ratna K. Vadlamudi, Rinath Jeselsohn, Virginia G. Kaklamani, Huai-Chin Chiang, Yiji Liao, Mei Yang, Tao Hong, Matias Amasino, Cecilia J. Proietti, Mauro E. Cenciarini, Zhao Zhang, and Yanming Wu

Abstract

This file contains eight supplementary figures depicting the experiments validated in different cell lines and cohorts, as well as the results supportive to the main text.

Published
2023

3. Data from Tamoxifen Resistance in Breast Cancer Is Regulated by the EZH2–ERα–GREB1 Transcriptional Axis

Author

Kexin Xu, Myles Brown, Rachel Schiff, Patricia V. Elizalde, Xiaoyong Fu, Carmine De Angelis, Rong Li, Tim Hui-Ming Huang, Ratna K. Vadlamudi, Rinath Jeselsohn, Virginia G. Kaklamani, Huai-Chin Chiang, Yiji Liao, Mei Yang, Tao Hong, Matias Amasino, Cecilia J. Proietti, Mauro E. Cenciarini, Zhao Zhang, and Yanming Wu

Abstract

Resistance to cancer treatment can be driven by epigenetic reprogramming of specific transcriptomes in favor of the refractory phenotypes. Here we discover that tamoxifen resistance in breast cancer is driven by a regulatory axis consisting of a master transcription factor, its cofactor, and an epigenetic regulator. The oncogenic histone methyltransferase EZH2 conferred tamoxifen resistance by silencing the expression of the estrogen receptor α (ERα) cofactor GREB1. In clinical specimens, induction of DNA methylation of a particular CpG-enriched region at the GREB1 promoter negatively correlated with GREB1 levels and cell sensitivity to endocrine agents. GREB1 also ensured proper cellular reactions to different ligands by recruiting distinct sets of ERα cofactors to cis-regulatory elements, which explains the contradictory biological effects of GREB1 on breast cancer cell growth in response to estrogen or antiestrogen. In refractory cells, EZH2-dependent repression of GREB1 triggered chromatin reallocation of ERα coregulators, converting the antiestrogen into an agonist. In clinical specimens from patients receiving adjuvant tamoxifen treatment, expression levels of EZH2 and GREB1 were correlated negatively, and taken together better predicted patient responses to endocrine therapy. Overall, our work suggests a new strategy to overcome endocrine resistance in metastatic breast cancer by targeting a particular epigenetic program.Significance: This study suggests a new strategy to overcome endocrine resistance in metastatic breast cancer by targeting a particular epigenetic program defined within. Cancer Res; 78(3); 671–84. ©2017 AACR.

Published
2023

4. Supplementary text from Tamoxifen Resistance in Breast Cancer Is Regulated by the EZH2–ERα–GREB1 Transcriptional Axis

Author

Kexin Xu, Myles Brown, Rachel Schiff, Patricia V. Elizalde, Xiaoyong Fu, Carmine De Angelis, Rong Li, Tim Hui-Ming Huang, Ratna K. Vadlamudi, Rinath Jeselsohn, Virginia G. Kaklamani, Huai-Chin Chiang, Yiji Liao, Mei Yang, Tao Hong, Matias Amasino, Cecilia J. Proietti, Mauro E. Cenciarini, Zhao Zhang, and Yanming Wu

Abstract

This file contains the supplementary information including materials and methods, primer sequences, clinicopathological characteristics of patient samples and supplemental figures legends.

Published
2023

5. Canonical ErbB-2 isoform and ErbB-2 variant c located in the nucleus drive triple negative breast cancer growth

Author

Nicolás Bellora, Franco Izzo, Rosalia Ines Cordo Russo, Pablo Guzmán, Juan Carlos Roa, Matías G. Pereyra, Mara De Martino, Mauro E. Cenciarini, Ezequiel Petrillo, Silvina Figurelli, Jose L. Daniotti, Daniel Lopez Della Vecchia, Osvaldo L. Podhajcer, Sabrina Barchuk, Lucía Santa María de la Parra, Patricia V. Elizalde, Violeta A. Chiauzzi, Cecilia J. Proietti, Leandro N. Guttlein, Roxana Schillaci, María F. Chervo, and Agustina Dupont

Subjects
0301 basic medicine, Gene isoform, Cancer Research, Receptor, ErbB-2, Otras Ciencias Biológicas, Triple Negative Breast Neoplasms, Receptor tyrosine kinase, Ciencias Biológicas, Transcriptome, 03 medical and health sciences, ErbB-2, Breast cancer, 0302 clinical medicine, ErbB, RNA interference, Cell Line, Tumor, Genetics, Humans, Protein Isoforms, Molecular Biology, Transcription factor, Mitogen-Activated Protein Kinase 7, Triple-negative breast cancer, Cell Proliferation, Cell Nucleus, Paraffin Embedding, biology, Alternative splicing, 030104 developmental biology, 030220 oncology & carcinogenesis, Cancer research, biology.protein, Female, TNBC, CIENCIAS NATURALES Y EXACTAS
Abstract

Triple negative breast cancer (TNBC) refers to tumors that do not express clinically significant levels of estrogen and progesterone receptors, and lack membrane overexpression or gene amplification of ErbB-2/HER2, a receptor tyrosine kinase. Transcriptome and proteome heterogeneity of TNBC poses a major challenge to precision medicine. Clinical biomarkers and targeted therapies for this disease remain elusive, so chemotherapy has been the standard of care for early and metastatic TNBC. Our present findings placed ErbB-2 in an unanticipated scenario: the nucleus of TNBC (NErbB-2). Our study on ErbB-2 alternative splicing events, using a PCR-sequencing approach combined with an RNA interference strategy, revealed that TNBC cells express either the canonical (wild-type) ErbB-2, encoded by transcript variant 1, or the non-canonical ErbB-2 isoform c, encoded by alternative variant 3 (RefSeq), or both. These ErbB-2 isoforms function in the nucleus as transcription factors. Evicting both from the nucleus or silencing isoform c only, blocks TN cell and tumor growth. This reveals not only NErbB-2 canonical and alternative isoforms role as targets of therapy in TNBC, but also isoform c dominant oncogenic potential. Furthermore, we validated our findings in the clinic and observed that NErbB-2 correlates with poor prognosis in primary TN tumors, disclosing NErbB-2 as a novel biomarker for TNBC. Our discoveries challenge the present scenario of drug development for personalized BC medicine that focuses on wild-type RefSeq proteins, which conserve the canonical domains and are located in their classical cellular compartments. Fil: Chervo, María Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Cordo Russo, Rosalia Ines. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Petrillo, Ezequiel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina Fil: Izzo, Franco. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: de Martino, Mara. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Bellora, Nicolás. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Patagonia Norte. Instituto Andino Patagónico de Tecnologías Biológicas y Geoambientales. Universidad Nacional del Comahue. Instituto Andino Patagónico de Tecnologías Biológicas y Geoambientales; Argentina Fil: Cenciarini, Mauro Ezequiel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Chiauzzi, Violeta Alicia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Santa María de la Parra, Lucía. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Pereyra Matías G.. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Güttlein, Leandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina Fil: Podhajcer, Osvaldo Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina Fil: Daniotti, Jose Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; Argentina Fil: Dupont, Agustina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Juan A. Fernández"; Argentina Fil: Barchuk, Sabrina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Juan A. Fernández"; Argentina Fil: Figurelli, Silvina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Juan A. Fernández"; Argentina Fil: Lopez Della Vecchia, Daniel Edgardo. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Juan A. Fernández"; Argentina Fil: Roa, Juan Carlos. Universidad de La Frontera. Núcleo Científico y Tecnológico en Recursos Naturales; Chile. Pontificia Universidad Católica de Chile; Chile Fil: Guzmán, Pablo. Universidad de La Frontera. Núcleo Científico y Tecnológico en Recursos Naturales; Chile Fil: Proietti Anastasi, Cecilia Jazmín. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Schillaci, Roxana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Elizalde, Patricia Virginia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina

Published
2020

6. SUN-122 Nuclear PDCD4 Expression Predicts Good Clinical Outcome in Luminal A-Like and Luminal B-Like Breast Cancer Subtypes

Author

Pablo Guzmán, Juan Carlos Roa, Silvina Figurelli, Agustina Roldán Deamicis, Rosalia Ines Cordo Russo, Leandro Venturutti, Mauro E. Cenciarini, Felipe G. Gercovich, Agustina Dupont, María F. Chervo, Violeta A. Chiauzzi, Santiago Madera, Sabrina Barchuk, Daniel Lopez Della Vecchia, Cecilia Jazmín Proietti Anastasi, Patricia V. Elizalde, Matías G. Pereyra, Roxana Schillaci, Sandra L. Ares, and Ernesto Gil Deza

Subjects
business.industry, Tumor Biology: Diagnostics, Therapies, Endocrine Neoplasias, and Hormone Dependent Tumors, Endocrinology, Diabetes and Metabolism, Cancer, Luminal a, Luminal b, medicine.disease, Breast cancer, Cancer research, medicine, Biomarker (medicine), Tumor Biology, business, AcademicSubjects/MED00250
Abstract

Hormone receptor-positive (HR+, estrogen and/or progesterone receptor-positive) and HER2-negative breast cancer (BC) subtype is a biologically heterogeneous entity that comprises 70% of BCs. This subtype includes both luminal (Lum) A- and B-like subtypes, which have differences in prognosis and sensitivity to endocrine therapies. The development of biomarkers guiding treatment decisions in these settings is required. Tumor suppressor PDCD4 (programmed cell death 4), which can be found both in the nucleus (NPDCD4) or the cytoplasm (CPDCD4), inhibits tumor growth and metastasis, and its loss is associated with poor prognosis in solid tumors. To explore the clinical relevance of PDCD4 in BC, we analyzed its expression by immunohistochemistry in a cohort of 619 patients with primary invasive BC. We found that 34.7% of patients showed NPDCD4 and 21.3% showed CPDCD4. NPDCD4 positivity, but not CPDCD4, was associated with lower clinical stage (P = 0.0003), with presence of more differentiated tumors (P = 6.4x10-6), and with estrogen and progesterone receptor (PR) expression (P = 9.2x10-9 and P = 2.8x10-9, respectively). Kaplan-Meier analysis revealed that NPDCD4 expression was associated with a longer overall survival (OS) and disease-free survival (DFS) in LumA-like (P = 0.008 and P = 0.028, respectively) and LumB-like (P = 0.004 and P = 0.012, respectively) subtypes. Interestingly, patients with LumB-like tumors displaying NPDCD4 presented estimated OS and DFS rates similar to the ones observed in patients with LumA-like tumors also expressing NPDCD4, indicating that its presence improves the clinical outcome of LumB-like patients. Multivariate Cox regression analysis identified NPDCD4 as an independent predictor of good clinical outcome in both LumA-like (HR: 0.45, 95% CI 0.22-0.96, P = 0.038) and LumB-like (HR: 0.28, 95% CI 0.10-0.80, P = 0.018) subtypes. We validated our results by in silico analysis using expression data from the METABRIC cohort. Bioinformatics analysis of BC cells from the Cancer Cell Line Encyclopedia revealed a positive correlation between PDCD4 and PR expression (P = 0.015). Since LumB-like tumors present a higher risk of resistance to endocrine therapy and both PR and PDCD4 levels in this subtype are lower than in the LumA-like one, we postulated that the presence of PR may modulate PDCD4 expression. Silencing of PR expression in HR+ cells decreased PDCD4 protein levels while reconstitution of PR in a PR-null cell line increased them, confirming PR requirement for PDCD4 modulation. In line with PDCD4 physiological function, its knockdown increased cell migration capability of HR+ BC cells, whereas its restoration led to a decrease in cell migration of HR-negative BC models. Our findings identified NPDCD4 positivity as a novel biomarker of clinical outcome in LumA- and B-like subtypes and revealed PDCD4 reconstitution as a novel therapeutic strategy in BC.

Published
2020

7. Nuclear PDCD4 Expression Defines a Subset of Luminal B-Like Breast Cancers with Good Prognosis

Author

Cecilia J. Proietti, Sandra L. Ares, Ernesto Gil Deza, Pablo Guzmán, Juan Carlos Roa, Agustina Dupont, Agustina Roldán Deamicis, Roxana Schillaci, Rosalia Ines Cordo Russo, Sabrina Barchuk, Franco Izzo, Felipe G. Gercovich, Matías G. Pereyra, Leandro Venturutti, Fabiana Anfuso, Patricia V. Elizalde, Eduardo Cortese, Teresa Castiglioni, Violeta A. Chiauzzi, Mauro E. Cenciarini, Santiago Madera, Gabriel Lebersztein, Silvina Figurelli, Claudio Levit, María F. Chervo, and Daniel Lopez Della Vecchia

Subjects
0301 basic medicine, Cancer Research, medicine.drug_class, Otras Ciencias Biológicas, Endocrinology, Diabetes and Metabolism, BIOMARKERS, Luma, Breast Neoplasms, Disease, HORMONE-DEPENDENT BREAST CANCER, Ciencias Biológicas, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Breast cancer, BREAST CANCER, Progesterone receptor, Medicine, Gene silencing, Humans, LUMINAL B-LIKE BREAST CANCER, PDCD4, Endocrine and Autonomic Systems, business.industry, RNA-Binding Proteins, medicine.disease, Prognosis, 030104 developmental biology, Oncology, Estrogen, 030220 oncology & carcinogenesis, Cancer research, Biomarker (medicine), Immunohistochemistry, Female, TUMOR SUPPRESSOR, business, Apoptosis Regulatory Proteins, CIENCIAS NATURALES Y EXACTAS
Abstract

The hormone receptor-positive (estrogen and/or progesterone receptor (PR)-positive) and HER2-negative breast cancer (BC) subtype is a biologically heterogeneous entity that includes luminal A-like (LumA-like) and luminal B-like (LumB-like) subtypes. Decreased PR levels is a distinctive biological feature of LumB-like tumors. These tumors also show reduced sensitivity to endocrine therapies and poorer prognosis than LumA-like tumors. Identification of biomarkers to accurately predict disease relapse in these subtypes is crucial in order to select effective therapies. We identified the tumor suppressor PDCD4 (programmed cell death 4), located in the nucleus (NPDCD4), as an independent prognostic factor of good clinical outcome in LumA-like and LumB-like subtypes. NPDCD4-positive LumB-like tumors presented overall and disease-free survival rates comparable to those of NPDCD4-positive LumA-like tumors, indicating that NPDCD4 improves the outcome of LumB-like patients. In contrast, NPDCD4 loss increased the risk of disease recurrence and death in LumB-like compared with LumA-like tumors. This, along with our results showing that LumB-like tumors present lower NPDCD4 positivity than LumA-like tumors, suggests that NPDCD4 loss contributes to endocrine therapy resistance in LumB-like BCs. We also revealed that PR induces PDCD4 transcription in LumB-like BC, providing a mechanistic explanation to the low PDCD4 levels in LumB-like BCs lacking PR. Finally, PDCD4 silencing enhanced BC cell survival in a patient-derived explant model of LumB-like disease. Our discoveries highlight NPDCD4 as a novel biomarker in LumA- and LumB-like subtypes, which could be included in the panel of immunohistochemical markers used in the clinic to accurately predict the prognosis of LumB-like tumors. Fil: Madera, Santiago. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Chervo, María Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Chiauzzi, Violeta Alicia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Pereyra Matías G.. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Venturutti, Leandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Izzo, Franco. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Roldán Deamicis, Agustina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Guzmán, Pablo. Universidad de La Frontera. Núcleo Científico y Tecnológico en Recursos Naturales; Chile Fil: Dupont, Agustina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Roa, Juan Carlos. Universidad de La Frontera. Núcleo Científico y Tecnológico en Recursos Naturales; Chile. Universidad Católica de Chile; Chile Fil: Cenciarini, Mauro Ezequiel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Barchuk, Sabrina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Juan A. Fernández"; Argentina Fil: Figurelli, Silvina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Juan A. Fernández"; Argentina Fil: Lopez Della Vecchia, Daniel Edgardo. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Juan A. Fernández"; Argentina Fil: Levit, Claudio. Sanatorio Sagrado Corazón. Servicio de Ginecología; Argentina Fil: Lebersztein, Gabriel. Sanatorio Sagrado Corazón. Servicio de Ginecología; Argentina Fil: Anfuso, Fabiana. Sanatorio Sagrado Corazón. Servicio de Ginecología; Argentina Fil: Castiglioni, Teresa. Centro de Patología Dr. Elsner; Argentina Fil: Cortese, Eduardo Mateo. Hospital Aeronáutico Central. Servicio de Ginecología; Argentina Fil: Ares, Sandra. Instituto Oncológico Henry Moore; Argentina Fil: Gil Deza, Ernesto. Instituto Oncológico Henry Moore; Argentina Fil: Gercovich, Felipe G.. Instituto Oncológico Henry Moore; Argentina Fil: Proietti Anastasi, Cecilia Jazmín. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Schillaci, Roxana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Cordo Russo, Rosalía I.. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Elizalde, Patricia Virginia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina

Published
2020

8. Blockade of Stat3 oncogene addiction induces cellular senescence and reveals a cell-nonautonomous activity suitable for cancer immunotherapy

Author

María F. Chervo, Darío Rocha, Mara De Martino, Roxana Schillaci, Damarys Loew, Patricia V. Elizalde, Eliane Piaggio, Elmer Andrés Fernández, Sofía Bruni, Cecilia J. Proietti, Florent Dingli, María Florencia Mercogliano, Mauro E. Cenciarini, and Mercedes Tkach

Subjects
STAT3 Transcription Factor, 0301 basic medicine, oncogene addiction, senescence, CIENCIAS MÉDICAS Y DE LA SALUD, medicine.medical_treatment, Immunology, Cell, Triple Negative Breast Neoplasms, Biology, stat3, STAT3, Mice, 03 medical and health sciences, 0302 clinical medicine, Immune system, Cancer immunotherapy, BREAST CANCER, medicine, Animals, Humans, Immunology and Allergy, IMMUNOTHERAPY, Melanoma, Cellular Senescence, RC254-282, Original Research, Otras Medicina Básica, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, purl.org/becyt/ford/3.1 [https], Immunotherapy, immune checkpoint blockade, RC581-607, Oncogene Addiction, medicine.disease, 3. Good health, Immunosurveillance, Medicina Básica, 030104 developmental biology, medicine.anatomical_structure, Oncology, SENESCENCE, 030220 oncology & carcinogenesis, Cancer cell, Cancer research, purl.org/becyt/ford/3 [https], immunotherapy, Immunologic diseases. Allergy
Abstract

Stat3 is constitutively activated in several tumor types and plays an essential role in maintaining their malignant phenotype and immunosupression. To take advantage of the promising antitumor activity of Stat3 targeting, it is vital to understand the mechanism by which Stat3 regulates both cell autonomous and non-autonomous processes. Here, we demonstrated that turning off Stat3 constitutive activation in different cancer cell types induces senescence, thus revealing their Stat3 addiction. Taking advantage of the senescence-associated secretory phenotype (SASP) induced by Stat3 silencing (SASP-siStat3), we designed an immunotherapy. The administration of SASP-siStat3 immunotherapy induced a strong inhibition of triplenegative breast cancer and melanoma growth associated with activation of CD4 + T and NK cells. Combining this immunotherapy with anti-PD-1 antibody resulted in survival improvement in mice bearing melanoma. The characterization of the SASP components revealed that type I IFN-related mediators, triggered by the activation of the cyclic GMP-AMP synthase DNA sensing pathway, are important for its immunosurveillance activity. Overall, our findings provided evidence that administration of SASP-siStat3 or low dose of Stat3- blocking agents would benefit patients with Stat3-addicted tumors to unleash an antitumor immune response and to improve the effectiveness of immune checkpoint inhibitors. Fil: de Martino, Mara. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Tkach, Mercedes. Institute Curie; Francia Fil: Bruni, Sofía. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Rocha, Darío Gastón. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales; Argentina Fil: Mercogliano, María Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Cenciarini, Mauro Ezequiel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Chervo, María Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Proietti Anastasi, Cecilia Jazmín. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Dingli, Florent. Institute Curie; Francia Fil: Loewy, Ruth Miriam. Institute Curie; Francia Fil: Fernández, Elmer A.. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigación y Desarrollo en Inmunología y Enfermedades Infecciosas. Universidad Católica de Córdoba. Centro de Investigación y Desarrollo en Inmunología y Enfermedades Infecciosas; Argentina Fil: Elizalde, Patricia Virginia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Piaggio, Eliane. Institute Curie; Francia Fil: Schillaci, Roxana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina

Published
2020

9. Molecular mechanisms underlying progesterone receptor action in breast cancer: Insights into cell proliferation and stem cell regulation

Author

Cecilia J. Proietti and Mauro E. Cenciarini

Subjects
CIENCIAS MÉDICAS Y DE LA SALUD, Clinical Biochemistry, 030209 endocrinology & metabolism, Breast Neoplasms, Biology, medicine.disease_cause, Biochemistry, 03 medical and health sciences, PROGESTERONE RECEPTOR, 0302 clinical medicine, Endocrinology, Breast cancer, BREAST CANCER, Progesterone receptor, medicine, Animals, Humans, Molecular Biology, Transcription factor, Cell Proliferation, Pharmacology, Cell growth, Organic Chemistry, MAMMARY GLAND, PROGESTERONE, Bioquímica y Biología Molecular, medicine.disease, Medicina Básica, Nuclear receptor, 030220 oncology & carcinogenesis, Cancer research, Neoplastic Stem Cells, Female, Signal transduction, Stem cell, Carcinogenesis, Receptors, Progesterone, STEM CELLS
Abstract

The ovarian steroid hormone progesterone and its nuclear receptor, the Progesterone Receptor (PR), play an essential role in the regulation of cell proliferation and differentiation in the mammary gland. In addition, experimental and clinical evidence demonstrate their critical role in controlling mammary gland tumorigenesis and breast cancer development. When bound to its ligand, the main action of PR is as a transcription factor, which regulates the expression of target genes networks. PR also activates signal transduction pathways through a rapid or non-genomic mechanism in breast cancer cells, an event that is fully integrated with its genomic effects. This review summarizes the molecular mechanisms of the ligand-activated PR actions that drive epithelial cell proliferation and the regulation of the stem cell population in the normal breast and in breast cancer. Fil: Cenciarini, Mauro Ezequiel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Proietti Anastasi, Cecilia Jazmín. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina

Published
2019

10. Tamoxifen resistance in breast cancer is regulated by the EZH2–ERa–GREB1 transcriptional axis

Author

Huai-Chin Chiang, Yanming Wu, Ratna K. Vadlamudi, Carmine De Angelis, Tao Hong, Xiaoyong Fu, Tim H M Huang, Rong Li, Kexin Xu, Patricia V. Elizalde, Cecilia J. Proietti, Zhao Zhang, Virginia G. Kaklamani, Mei Yang, Yiji Liao, Rachel Schiff, Mauro E. Cenciarini, Rinath Jeselsohn, Myles Brown, Matias Amasino, Wu, Y., Zhang, Z., Cenciarini, M. E., Proietti, C. J., Amasino, M., Hong, T., Yang, M., Liao, Y., Chiang, H. -C., Kaklamani, V. G., Jeselsohn, R., Vadlamudi, R. K., Huang, T. H. -M., Li, R., De Angelis, C., Fu, X., Elizalde, P. V., Schiff, R., Brown, M., and Xu, K.

Subjects
0301 basic medicine, Cancer Research, endocrine system diseases, Transcription, Genetic, Carcinogenesis, Estrogen receptor, Apoptosis, medicine.disease_cause, Epigenesis, Genetic, Mice, Tumor Cells, Cultured, Promoter Regions, Genetic, Carcinogenesi, DNA methylation, EZH2, Estrogen Antagonists, Tamoxifen resistance, purl.org/becyt/ford/3.1 [https], Estrogen Antagonist, Prognosis, Neoplasm Proteins, Gene Expression Regulation, Neoplastic, Oncology, Histone methyltransferase, purl.org/becyt/ford/3 [https], Female, Breast Neoplasm, medicine.drug, Human, Xenograft Model Antitumor Assay, Prognosi, Mice, Nude, Breast Neoplasms, Biology, Article, Follow-Up Studie, Neoplasm Protein, 03 medical and health sciences, medicine, Biomarkers, Tumor, Animals, Humans, Enhancer of Zeste Homolog 2 Protein, Cell Proliferation, Epigenetic therapy, Animal, Estrogen Receptor alpha, Apoptosi, DNA Methylation, Antiestrogen, Xenograft Model Antitumor Assays, GREB1, ERalpha signaling, Tamoxifen, 030104 developmental biology, Drug Resistance, Neoplasm, Cancer research, Estrogen receptor alpha, Follow-Up Studies
Abstract

Resistance to cancer treatment can be driven by epigenetic reprogramming of specific transcriptomes in favor of the refractory phenotypes. Here we discover that tamoxifen resistance in breast cancer is driven by a regulatory axis consisting of a master transcription factor, its cofactor, and an epigenetic regulator. The oncogenic histone methyltransferase EZH2 conferred tamoxifen resistance by silencing the expression of the estrogen receptor a (ERa) cofactor GREB1. In clinical specimens, induction of DNA methylation of a particular CpG-enriched region at the GREB1 promoter negatively correlated with GREB1 levels and cell sensitivity to endocrine agents. GREB1 also ensured proper cellular reactions to different ligands by recruiting distinct sets of ERa cofactors to cis-regulatory elements, which explains the contradictory biological effects of GREB1 on breast cancer cell growth in response to estrogen or antiestrogen. In refractory cells, EZH2-dependent repression of GREB1 triggered chromatin reallocation of ERa coregulators, converting the antiestrogen into an agonist. In clinical specimens from patients receiving adjuvant tamoxifen treatment, expression levels of EZH2 and GREB1 were correlated negatively, and taken together better predicted patient responses to endocrine therapy. Overall, our work suggests a new strategy to overcome endocrine resistance in metastatic breast cancer by targeting a particular epigenetic program. Significance: This study suggests a new strategy to overcome endocrine resistance in metastatic breast cancer by targeting a particular epigenetic program defined within. Fil: Wu, Yanming. University of Texas at San Antonio; Estados Unidos Fil: Zhang, Zhao. University of Texas at San Antonio; Estados Unidos Fil: Cenciarini, Mauro Ezequiel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Proietti Anastasi, Cecilia Jazmín. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Amasino, Matías Federico. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Hong, Tao. University of Texas at San Antonio; Estados Unidos. Central South University; China Fil: Yang, Mei. University of Texas at San Antonio; Estados Unidos Fil: Liao, Yiji. University of Texas at San Antonio; Estados Unidos Fil: Chiang, Huai-Chin. University of Texas at San Antonio; Estados Unidos. University Of Texas Health Science Center At San Antonio (ut Health San Antonio) ; University Of Texas At San Antonio; Fil: Kaklamani, Virginia G.. University Of Texas Health Science Center At San Antonio (ut Health San Antonio) ; University Of Texas At San Antonio; Fil: Jeselsohn, Rinath. Dana-farber Cancer Institute; Estados Unidos Fil: Vadlamudi, Ratna K.. University Of Texas Health Science Center At San Antonio (ut Health San Antonio) ; University Of Texas At San Antonio; Fil: Huang, Tim Hui Ming. University Of Texas Health Science Center At San Antonio (ut Health San Antonio) ; University Of Texas At San Antonio; Fil: Li, Rong. University Of Texas Health Science Center At San Antonio (ut Health San Antonio) ; University Of Texas At San Antonio; Fil: De Angelis, Carmine. Baylor College Of Medicine; Estados Unidos Fil: Fu, Xiaoyong. Baylor College Of Medicine; Estados Unidos Fil: Elizalde, Patricia Virginia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Schiff, Rachel. Baylor College Of Medicine; Estados Unidos Fil: Brown, Myles. Dana farber Cancer Institute; Estados Unidos Fil: Xu, Kexin. University Of Texas Health Science Center At San Antonio (ut Health San Antonio) ; University Of Texas At San Antonio

Published
2018

11. Revisiting progesterone receptor (PR) actions in breast cancer: Insights into PR repressive functions

Author

Cecilia J. Proietti, Patricia V. Elizalde, and Mauro E. Cenciarini

Subjects
0301 basic medicine, Transcription, Genetic, medicine.medical_treatment, Clinical Biochemistry, Breast Neoplasms, Biology, Biochemistry, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Breast cancer, Progesterone receptor, medicine, Animals, Humans, Molecular Biology, Psychological repression, Transcription factor, Pharmacology, Organic Chemistry, Master regulator, medicine.disease, Chromatin, Steroid hormone, 030104 developmental biology, Nuclear receptor, 030220 oncology & carcinogenesis, Cancer research, Receptors, Progesterone
Abstract

Progesterone receptor (PR) is a master regulator in female reproductive tissues that controls developmental processes and proliferation and differentiation during the reproductive cycle and pregnancy. PR also plays a role in progression of endocrine-dependent breast cancer. As a member of the nuclear receptor family of ligand-dependent transcription factors, the main action of PR is to regulate networks of target gene expression in response to binding its cognate steroid hormone, progesterone. Liganded-PR transcriptional activation has been thoroughly studied and associated mechanisms have been described while progesterone-mediated repression has remained less explored. The present work summarizes recent advances in the understanding of how PR-mediated repression is accomplished in breast cancer cells and highlights the significance of fully understanding the determinants of context-dependent PR action.

Published
2017

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