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Article ; Online: Therapeutic Potential of Tumor Metabolic Reprogramming in Triple-Negative Breast Cancer.

Munkácsy, Gyöngyi / Santarpia, Libero / Győrffy, Balázs

International journal of molecular sciences

2023 Volume 24, Issue 8

Abstract: Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, with clinical features of high metastatic potential, susceptibility to relapse, and poor prognosis. TNBC lacks the expression of the estrogen receptor (ER), ... ...

Abstract	Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, with clinical features of high metastatic potential, susceptibility to relapse, and poor prognosis. TNBC lacks the expression of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). It is characterized by genomic and transcriptional heterogeneity and a tumor microenvironment (TME) with the presence of high levels of stromal tumor-infiltrating lymphocytes (TILs), immunogenicity, and an important immunosuppressive landscape. Recent evidence suggests that metabolic changes in the TME play a key role in molding tumor development by impacting the stromal and immune cell fractions, TME composition, and activation. Hence, a complex inter-talk between metabolic and TME signaling in TNBC exists, highlighting the possibility of uncovering and investigating novel therapeutic targets. A better understanding of the interaction between the TME and tumor cells, and the underlying molecular mechanisms of cell-cell communication signaling, may uncover additional targets for better therapeutic strategies in TNBC treatment. In this review, we aim to discuss the mechanisms in tumor metabolic reprogramming, linking these changes to potential targetable molecular mechanisms to generate new, physical science-inspired clinical translational insights for the cure of TNBC.
MeSH term(s)	Humans ; Triple Negative Breast Neoplasms/therapy ; Triple Negative Breast Neoplasms/drug therapy ; Neoplasm Recurrence, Local ; Signal Transduction ; Receptors, Estrogen/metabolism ; Tumor Microenvironment
Chemical Substances	Receptors, Estrogen
Language	English
Publishing date	2023-04-08
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms24086945
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Article: Gene Expression Profiling in Early Breast Cancer-Patient Stratification Based on Molecular and Tumor Microenvironment Features.

Munkácsy, Gyöngyi / Santarpia, Libero / Győrffy, Balázs

Biomedicines

2022 Volume 10, Issue 2

Abstract: Patients with early-stage hormone receptor-positive, human epidermal growth factor receptor 2-negative (HER2-) breast cancer (BC) are typically treated with surgery, followed by adjuvant systemic endocrine therapy with or without adjuvant chemotherapy ... ...

Abstract	Patients with early-stage hormone receptor-positive, human epidermal growth factor receptor 2-negative (HER2-) breast cancer (BC) are typically treated with surgery, followed by adjuvant systemic endocrine therapy with or without adjuvant chemotherapy and radiation therapy. Current guidelines regarding the use of adjuvant systemic therapy depend on clinical and pathological factors, such as the morphological assessment of tumor subtype; histological grade; tumor size; lymphovascular invasion; and lymph node status combined with estrogen receptor, progesterone receptor, and HER2 biomarker profiles assessed using immunohistochemistry and in situ hybridization. Additionally, the prognostic and predictive value of tumor-infiltrating lymphocytes and their composition is emerging as a key marker in triple negative (TNBC) and HER2-enriched molecular breast tumor subtypes. However, all these factors do not necessarily reflect the molecular heterogeneity and complexity of breast cancer. In the last two decades, gene expression signatures or profiling (GEP) tests have been developed to predict the risk of disease recurrence and estimate the potential benefit of receiving adjuvant systemic chemotherapy in patients with luminal breast cancer. GEPs have been utilized to help physicians to refine decision-making process, complementing clinicopathological parameters, and can now be used to classify the risk of recurrence and tailoring personalized treatments. Several clinical trials using GEPs validate the increasing value of such assays in different clinical settings, addressing relevant clinical endpoints. Finally, the recent approval of immune checkpoint inhibitors in TNBC and the increasing use of immunotherapy in different molecular BC populations highlight the opportunity to refine current GEPs by including a variety of immune-related genes that may help to improve predicting drug response and finetune prognosis.
Language	English
Publishing date	2022-01-24
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2720867-9
ISSN	2227-9059
ISSN	2227-9059
DOI	10.3390/biomedicines10020248
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Article ; Online: Gene Expression Profiling in Early Breast Cancer—Patient Stratification Based on Molecular and Tumor Microenvironment Features

Gyöngyi Munkácsy / Libero Santarpia / Balázs Győrffy

Biomedicines, Vol 10, Iss 248, p

2022 Volume 248

Abstract: Patients with early-stage hormone receptor-positive, human epidermal growth factor receptor 2-negative (HER2−) breast cancer (BC) are typically treated with surgery, followed by adjuvant systemic endocrine therapy with or without adjuvant chemotherapy ... ...

Abstract	Patients with early-stage hormone receptor-positive, human epidermal growth factor receptor 2-negative (HER2−) breast cancer (BC) are typically treated with surgery, followed by adjuvant systemic endocrine therapy with or without adjuvant chemotherapy and radiation therapy. Current guidelines regarding the use of adjuvant systemic therapy depend on clinical and pathological factors, such as the morphological assessment of tumor subtype; histological grade; tumor size; lymphovascular invasion; and lymph node status combined with estrogen receptor, progesterone receptor, and HER2 biomarker profiles assessed using immunohistochemistry and in situ hybridization. Additionally, the prognostic and predictive value of tumor-infiltrating lymphocytes and their composition is emerging as a key marker in triple negative (TNBC) and HER2-enriched molecular breast tumor subtypes. However, all these factors do not necessarily reflect the molecular heterogeneity and complexity of breast cancer. In the last two decades, gene expression signatures or profiling (GEP) tests have been developed to predict the risk of disease recurrence and estimate the potential benefit of receiving adjuvant systemic chemotherapy in patients with luminal breast cancer. GEPs have been utilized to help physicians to refine decision-making process, complementing clinicopathological parameters, and can now be used to classify the risk of recurrence and tailoring personalized treatments. Several clinical trials using GEPs validate the increasing value of such assays in different clinical settings, addressing relevant clinical endpoints. Finally, the recent approval of immune checkpoint inhibitors in TNBC and the increasing use of immunotherapy in different molecular BC populations highlight the opportunity to refine current GEPs by including a variety of immune-related genes that may help to improve predicting drug response and finetune prognosis.
Keywords	adjuvant chemotherapy ; classification ; early breast cancer ; gene expression profiling ; immune-related genes ; predictive ; Biology (General) ; QH301-705.5
Subject code	610 ; 616
Language	English
Publishing date	2022-01-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
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Article ; Online: Progress in nonviral gene therapy for breast cancer and what comes next?

Bottai, Giulia / Truffi, Marta / Corsi, Fabio / Santarpia, Libero

Expert opinion on biological therapy

2017 Volume 17, Issue 5, Page(s) 595–611

Abstract: Introduction: The possibility of correcting defective genes and modulating gene expression through gene therapy has emerged as a promising treatment strategy for breast cancer. Furthermore, the relevance of tumor immune microenvironment in supporting ... ...

Abstract	Introduction: The possibility of correcting defective genes and modulating gene expression through gene therapy has emerged as a promising treatment strategy for breast cancer. Furthermore, the relevance of tumor immune microenvironment in supporting the oncogenic process has paved the way for novel immunomodulatory applications of gene therapy. Areas covered: In this review, the authors describe the most relevant delivery systems, focusing on nonviral vectors, along with the description of the major approaches used to modify target cells, including gene transfer, RNA interference (RNAi), and epigenetic regulation. Furthermore, they highlight innovative therapeutic strategies and the application of gene therapy in clinical trials for breast cancer. Expert opinion: Gene therapy has the potential to impact breast cancer research. Further efforts are required to increase the clinical application of RNAi-based therapeutics, especially in combination with conventional treatments. Innovative strategies, including genome editing and stem cell-based systems, may contribute to translate gene therapy into clinical practice. Immune-based approaches have emerged as an attractive therapeutic opportunity for selected breast cancer patients. However, several challenges need to be addressed before considering gene therapy as an actual option for the treatment of breast cancer.
MeSH term(s)	Animals ; Breast Neoplasms/genetics ; Breast Neoplasms/immunology ; Breast Neoplasms/therapy ; Carcinogenesis/genetics ; Carcinogenesis/immunology ; Clinical Trials as Topic/methods ; Epigenesis, Genetic/genetics ; Epigenesis, Genetic/immunology ; Female ; Genetic Therapy/methods ; Genetic Therapy/trends ; Humans ; Oncogenes/genetics ; Oncogenes/immunology ; RNA Interference/physiology ; Tumor Microenvironment/genetics ; Tumor Microenvironment/immunology
Language	English
Publishing date	2017-05
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2052501-1
ISSN	1744-7682 ; 1471-2598
ISSN (online)	1744-7682
ISSN	1471-2598
DOI	10.1080/14712598.2017.1305351
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Zs.A 6094: Show issues

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Article ; Online: Role of inflammation in obesity-related breast cancer.

Crespi, Elisa / Bottai, Giulia / Santarpia, Libero

Current opinion in pharmacology

2016 Volume 31, Page(s) 114–122

Abstract: Chronic inflammation associated with obesity is now recognized to be an important condition in promoting carcinogenesis and progression in breast cancer patients, mostly in postmenopausal women with tumors expressing estrogen and progesterone receptors. ... ...

Abstract	Chronic inflammation associated with obesity is now recognized to be an important condition in promoting carcinogenesis and progression in breast cancer patients, mostly in postmenopausal women with tumors expressing estrogen and progesterone receptors. In obese patients, altered levels of several inflammatory mediators regulating aromatase and estrogen expression are one of the mechanisms responsible of increase breast cancer risk. Growing attention has also been paid to the local adipose inflammation and the role played by macrophages as determinants of breast cancer risk recurrence and prognosis. The inflammation-obesity axis offers different molecular signaling pathways for therapeutic interventions and potential pharmacological targets. The increasing rate of obesity worldwide associated with the recent findings linking inflammation and breast cancer urge further investigation.
MeSH term(s)	Animals ; Breast Neoplasms/drug therapy ; Breast Neoplasms/etiology ; Breast Neoplasms/pathology ; Chronic Disease ; Disease Progression ; Drug Design ; Estrogens/metabolism ; Female ; Humans ; Inflammation/complications ; Inflammation/etiology ; Inflammation/pathology ; Inflammation Mediators/metabolism ; Macrophages/metabolism ; Obesity/complications ; Receptors, Progesterone/metabolism ; Signal Transduction
Chemical Substances	Estrogens ; Inflammation Mediators ; Receptors, Progesterone
Language	English
Publishing date	2016-12
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2037057-X
ISSN	1471-4973 ; 1471-4892
ISSN (online)	1471-4973
ISSN	1471-4892
DOI	10.1016/j.coph.2016.11.004
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Zs.A 5608: Show issues

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Article ; Online: Inhibition of RET activated pathways: novel strategies for therapeutic intervention in human cancers.

Santarpia, Libero / Bottai, Giulia

Current pharmaceutical design

2012 Volume 19, Issue 5, Page(s) 864–882

Abstract: The REarranged during Transfection (RET) proto-oncogene and its activated signalling pathways have been shown to play an important role in cancer. RET genetic alterations including germline, somatic mutations and gene rearrangements have been ... ...

Abstract	The REarranged during Transfection (RET) proto-oncogene and its activated signalling pathways have been shown to play an important role in cancer. RET genetic alterations including germline, somatic mutations and gene rearrangements have been demonstrated in several solid tumours, and numerous clinical trials using multikinase inhibitors containing RET as a target have shown significant activity against RET. Sorafenib and sunitinib have been approved for the treatment of renal, hepatocellular, gastrointestinal and pancreatic neuoendocrine carcinomas. Vandetanib has recently been approved for the treatment of unresectable locally advanced or metastatic medullary thyroid carcinomas. Novel genomic rearrangements and RET signalling interactions are now being studied in a variety of tumours and will provide the basis for new therapeutic strategies. Combination or sequential targeted therapies that are based on solid preclinical data regarding the inhibition of RET-mediated parallel or different -signalling pathways will likely be more effective.
MeSH term(s)	Animals ; Antineoplastic Agents/pharmacology ; Drug Design ; Humans ; Indoles/pharmacology ; Molecular Targeted Therapy ; Neoplasms/drug therapy ; Neoplasms/genetics ; Neoplasms/pathology ; Niacinamide/analogs & derivatives ; Niacinamide/pharmacology ; Phenylurea Compounds/pharmacology ; Piperidines/pharmacology ; Proto-Oncogene Mas ; Proto-Oncogene Proteins c-ret/genetics ; Proto-Oncogene Proteins c-ret/metabolism ; Pyrroles/pharmacology ; Quinazolines/pharmacology ; Signal Transduction/drug effects ; Sorafenib ; Sunitinib
Chemical Substances	Antineoplastic Agents ; Indoles ; MAS1 protein, human ; Phenylurea Compounds ; Piperidines ; Proto-Oncogene Mas ; Pyrroles ; Quinazolines ; Niacinamide (25X51I8RD4) ; Sorafenib (9ZOQ3TZI87) ; Proto-Oncogene Proteins c-ret (EC 2.7.10.1) ; Sunitinib (V99T50803M) ; vandetanib (YO460OQ37K)
Language	English
Publishing date	2012-08-14
Publishing country	United Arab Emirates
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1304236-1
ISSN	1873-4286 ; 1381-6128
ISSN (online)	1873-4286
ISSN	1381-6128
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Zs.A 4714: Show issues

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Article ; Online: A Comprehensive Outline of Trastuzumab Resistance Biomarkers in HER2 Overexpressing Breast Cancer.

Menyhárt, Otília / Santarpia, Libero / Győrffy, Balázs

Current cancer drug targets

2015 Volume 15, Issue 8, Page(s) 665–683

Abstract: The introduction of trastuzumab for anti-HER2 therapy dramatically changed the clinical outcome for HER2 (ERBB2, neu) positive breast cancer patients. Today, patients eligible for trastuzumab are selected using HER2 expression/amplification status of the ...

Abstract	The introduction of trastuzumab for anti-HER2 therapy dramatically changed the clinical outcome for HER2 (ERBB2, neu) positive breast cancer patients. Today, patients eligible for trastuzumab are selected using HER2 expression/amplification status of the primary tumor. However, acquired and inherent resistance to anti-HER2 therapy in these patients poses a significant challenge, and better patient stratification will be needed to improve clinical response. Here, we provide a wide-ranging overview of potential biomarkers capable of stratifying patients regarding their response to trastuzumab. These include HER2 amplification, impaired access to the binding site (p95HER2, Δ16HER-2, MUC4), augmented signaling through other ERBB family receptors (HER1, HER3, HER4) and their ligands, activation of HER2 targets by alternate heterodimers (EphA2, IGF-1R, GDF15, MUC1*), signaling triggered by downstream members (PIK3CA, PTEN, SRC, mTOR), altered expression of cell cycle and apoptotic regulators (CDKs, p27(kip1), Bcl-2), hormone receptor status, resistance to antibody-dependent cellular cytotoxicity (FcγR), and altered miRNA expression signatures. Multigenic molecular profile analyses have revealed further genes not directly associated with classical oncogenic pathways. Although numerous biomarkers have shown promise in pre-clinical studies, many have delivered controversial results when evaluated in clinical trials. One of the keys for targeting ERBB2 will be to consider the entire ERBB family and downstream associated pathways responsible for the malignant transformation. The heterogeneity of the disease is likely to represent a significant obstacle to accurately predicting the course of resistance. The future most probably involves the incorporation of multiple biomarkers into a unified predictor enabling selection of patients for superior targeted drug administration.
MeSH term(s)	Antineoplastic Agents/therapeutic use ; Biomarkers/analysis ; Breast Neoplasms/drug therapy ; Breast Neoplasms/genetics ; Breast Neoplasms/metabolism ; Drug Resistance, Neoplasm ; Female ; Humans ; Receptor, ErbB-2/biosynthesis ; Receptor, ErbB-2/genetics ; Trastuzumab/therapeutic use
Chemical Substances	Antineoplastic Agents ; Biomarkers ; ERBB2 protein, human (EC 2.7.10.1) ; Receptor, ErbB-2 (EC 2.7.10.1) ; Trastuzumab (P188ANX8CK)
Language	English
Publishing date	2015-09-23
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2064824-8
ISSN	1873-5576 ; 1568-0096
ISSN (online)	1873-5576
ISSN	1568-0096
DOI	10.2174/156800961508151001101742
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Zs.A 5589: Show issues

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Article: Cellular signaling pathway alterations and potential targeted therapies for medullary thyroid carcinoma.

Giunti, Serena / Antonelli, Alessandro / Amorosi, Andrea / Santarpia, Libero

International journal of endocrinology

2013 Volume 2013, Page(s) 803171

Abstract: Parafollicular C-cell-derived medullary thyroid cancer (MTC) comprises 3% to 4% of all thyroid cancers. While cytotoxic treatments have been shown to have limited efficacy, targeted molecular therapies that inhibit rearranged during transfection (RET) ... ...

Abstract	Parafollicular C-cell-derived medullary thyroid cancer (MTC) comprises 3% to 4% of all thyroid cancers. While cytotoxic treatments have been shown to have limited efficacy, targeted molecular therapies that inhibit rearranged during transfection (RET) and other tyrosine kinase receptors that are mainly involved in angiogenesis have shown great promise in the treatment of metastatic or locally advanced MTC. Multi-tyrosine kinase inhibitors such as vandetanib, which is already approved for the treatment of progressive MTC, and cabozantinib have shown distinct advantages with regard to rates of disease response and control. However, these types of tyrosine kinase inhibitor compounds are able to concurrently block several types of targets, which limits the understanding of RET as a specific target. Moreover, important resistances to tyrosine kinase inhibitors can occur, which limit the long-term efficacy of these treatments. Deregulated cellular signaling pathways and genetic alterations in MTC, particularly the activation of the RAS/mammalian target of rapamycin (mTOR) cascades and RET crosstalk signaling, are now emerging as novel and potentially promising therapeutic treatments for aggressive MTC.
Language	English
Publishing date	2013-02-21
Publishing country	Egypt
Document type	Journal Article
ZDB-ID	2502951-4
ISSN	1687-8345 ; 1687-8337
ISSN (online)	1687-8345
ISSN	1687-8337
DOI	10.1155/2013/803171
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Article ; Online: Cellular Signaling Pathway Alterations and Potential Targeted Therapies for Medullary Thyroid Carcinoma

Serena Giunti / Alessandro Antonelli / Andrea Amorosi / Libero Santarpia

International Journal of Endocrinology, Vol

2013 Volume 2013

Keywords	Diseases of the endocrine glands. Clinical endocrinology ; RC648-665 ; Specialties of internal medicine ; RC581-951 ; Internal medicine ; RC31-1245 ; Medicine ; R ; DOAJ:Internal medicine ; DOAJ:Medicine (General) ; DOAJ:Health Sciences
Language	English
Publishing date	2013-01-01T00:00:00Z
Publisher	Hindawi Publishing Corporation
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: miRpower: a web-tool to validate survival-associated miRNAs utilizing expression data from 2178 breast cancer patients.

Lánczky, András / Nagy, Ádám / Bottai, Giulia / Munkácsy, Gyöngyi / Szabó, András / Santarpia, Libero / Győrffy, Balázs

Breast cancer research and treatment

2016 Volume 160, Issue 3, Page(s) 439–446

Abstract: Purpose: The proper validation of prognostic biomarkers is an important clinical issue in breast cancer research. MicroRNAs (miRNAs) have emerged as a new class of promising breast cancer biomarkers. In the present work, we developed an integrated ... ...

Abstract	Purpose: The proper validation of prognostic biomarkers is an important clinical issue in breast cancer research. MicroRNAs (miRNAs) have emerged as a new class of promising breast cancer biomarkers. In the present work, we developed an integrated online bioinformatic tool to validate the prognostic relevance of miRNAs in breast cancer. Methods: A database was set up by searching the GEO, EGA, TCGA, and PubMed repositories to identify datasets with published miRNA expression and clinical data. Kaplan-Meier survival analysis was performed to validate the prognostic value of a set of 41 previously published survival-associated miRNAs. Results: All together 2178 samples from four independent datasets were integrated into the system including the expression of 1052 distinct human miRNAs. In addition, the web-tool allows for the selection of patients, which can be filtered by receptors status, lymph node involvement, histological grade, and treatments. The complete analysis tool can be accessed online at: www.kmplot.com/mirpower . We used this tool to analyze a large number of deregulated miRNAs associated with breast cancer features and outcome, and confirmed the prognostic value of 26 miRNAs. A significant correlation in three out of four datasets was validated only for miR-29c and miR-101. Conclusions: In summary, we established an integrated platform capable to mine all available miRNA data to perform a survival analysis for the identification and validation of prognostic miRNA markers in breast cancer.
Language	English
Publishing date	2016-12
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	604563-7
ISSN	1573-7217 ; 0167-6806
ISSN (online)	1573-7217
ISSN	0167-6806
DOI	10.1007/s10549-016-4013-7
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