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

IF 3 4区 医学 Q3 Biochemistry, Genetics and Molecular Biology Hormones & Cancer Pub Date : 2020-10-01 DOI:10.1007/s12672-020-00392-4
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
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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.

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核PDCD4表达定义了一个预后良好的腔内b样乳腺癌亚群
激素受体阳性(雌激素和/或孕激素受体(PR)阳性)和her2阴性乳腺癌(BC)亚型是一种生物学异质性实体,包括腔内a样(luma样)和腔内b样(lumb样)亚型。PR水平降低是腰样肿瘤的显著生物学特征。这些肿瘤对内分泌治疗的敏感性也较低,预后较肿瘤样肿瘤差。鉴定生物标志物以准确预测这些亚型的疾病复发对于选择有效的治疗方法至关重要。我们发现位于细胞核(NPDCD4)的肿瘤抑制因子PDCD4(程序性细胞死亡4)是luma样和lumb样亚型良好临床结果的独立预后因素。NPDCD4阳性的LumB-like肿瘤的总体生存率和无病生存率与NPDCD4阳性的LumA-like肿瘤相当,表明NPDCD4改善了LumB-like患者的预后。相比之下,与luma样肿瘤相比,NPDCD4缺失增加了lumb样肿瘤复发和死亡的风险。这一点,再加上我们的研究结果显示,lumb样肿瘤的NPDCD4阳性水平低于luma样肿瘤,表明NPDCD4缺失有助于lumb样bc的内分泌治疗抵抗。我们还发现,PR在LumB-like BC中诱导PDCD4转录,为缺乏PR的LumB-like BC中PDCD4水平低提供了机制解释。最后,在患者来源的LumB-like疾病外植体模型中,PDCD4沉默提高了BC细胞存活率。我们的发现突出了NPDCD4作为LumA-和lumb -样亚型的一种新的生物标志物,它可以被纳入临床使用的免疫组织化学标志物中,以准确预测lumb -样肿瘤的预后。
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来源期刊
Hormones & Cancer
Hormones & Cancer ONCOLOGY-ENDOCRINOLOGY & METABOLISM
CiteScore
4.60
自引率
0.00%
发文量
0
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.
期刊最新文献
Welcome from the new Discover Oncology journal : Editorial - 28th December, 2020. Nuclear PDCD4 Expression Defines a Subset of Luminal B-Like Breast Cancers with Good Prognosis. Prevalence of Histological Characteristics of Breast Cancer in Rwanda in Relation to Age and Tumor Stages. The Thyroid Tumor Microenvironment: Potential Targets for Therapeutic Intervention and Prognostication. Outcome of Clinical Genetic Testing in Patients with Features Suggestive for Hereditary Predisposition to PTH-Mediated Hypercalcemia.
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