Santiago Madera, María F Chervo, Violeta A Chiauzzi, Matías G Pereyra, Leandro Venturutti, Franco Izzo, Agustina Roldán Deamicis, Pablo Guzman, Agustina Dupont, Juan Carlos Roa, Mauro E Cenciarini, Sabrina Barchuk, Silvina Figurelli, Daniel Lopez Della Vecchia, Claudio Levit, Gabriel Lebersztein, Fabiana Anfuso, Teresa Castiglioni, Eduardo Cortese, Sandra Ares, Ernesto Gil Deza, Felipe G Gercovich, Cecilia J Proietti, Roxana Schillaci, Rosalía I Cordo Russo, Patricia V Elizalde
{"title":"Nuclear PDCD4 Expression Defines a Subset of Luminal B-Like Breast Cancers with Good Prognosis.","authors":"Santiago Madera, María F Chervo, Violeta A Chiauzzi, Matías G Pereyra, Leandro Venturutti, Franco Izzo, Agustina Roldán Deamicis, Pablo Guzman, Agustina Dupont, Juan Carlos Roa, Mauro E Cenciarini, Sabrina Barchuk, Silvina Figurelli, Daniel Lopez Della Vecchia, Claudio Levit, Gabriel Lebersztein, Fabiana Anfuso, Teresa Castiglioni, Eduardo Cortese, Sandra Ares, Ernesto Gil Deza, Felipe G Gercovich, Cecilia J Proietti, Roxana Schillaci, Rosalía I Cordo Russo, Patricia V Elizalde","doi":"10.1007/s12672-020-00392-4","DOIUrl":null,"url":null,"abstract":"<p><p>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.</p>","PeriodicalId":13060,"journal":{"name":"Hormones & Cancer","volume":null,"pages":null},"PeriodicalIF":3.0000,"publicationDate":"2020-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/s12672-020-00392-4","citationCount":"7","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Hormones & Cancer","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s12672-020-00392-4","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"Biochemistry, Genetics and Molecular Biology","Score":null,"Total":0}
引用次数: 7
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.
期刊介绍:
Hormones and Cancer is a unique multidisciplinary translational journal featuring basic science, pre-clinical, epidemiological, and clinical research papers. It covers all aspects of the interface of Endocrinology and Oncology. Thus, the journal covers two main areas of research: Endocrine tumors (benign & malignant tumors of hormone secreting endocrine organs) and the effects of hormones on any type of tumor. We welcome all types of studies related to these fields, but our particular attention is on translational aspects of research. In addition to basic, pre-clinical, and epidemiological studies, we encourage submission of clinical studies including those that comprise small series of tumors in rare endocrine neoplasias and/or negative or confirmatory results provided that they significantly enhance our understanding of endocrine aspects of oncology. The journal does not publish case studies.