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15 pages, 2653 KiB

Open AccessArticle

Multi-Omics Approach Points to the Importance of Oxylipins Metabolism in Early-Stage Breast Cancer

by Dmitry V. Chistyakov, Mariia V. Guryleva, Elena S. Stepanova, Lyubov M. Makarenkova, Elena V. Ptitsyna, Sergei V. Goriainov, Arina I. Nikolskaya, Alina A. Astakhova, Anna S. Klimenko, Olga A. Bezborodova, Elena A. Rasskazova, Olga G. Potanina, Rimma A. Abramovich, Elena R. Nemtsova and Marina G. Sergeeva

Cancers 2022, 14(8), 2041; https://doi.org/10.3390/cancers14082041 - 18 Apr 2022

Cited by 16 | Viewed by 3235

Abstract

The involvement of oxylipins, metabolites of polyunsaturated fatty acids, in cancer pathogenesis was known long ago, but only the development of the high-throughput methods get the opportunity to study oxylipins on a system level. The study aimed to elucidate alterations in oxylipin metabolism [...] Read more.

The involvement of oxylipins, metabolites of polyunsaturated fatty acids, in cancer pathogenesis was known long ago, but only the development of the high-throughput methods get the opportunity to study oxylipins on a system level. The study aimed to elucidate alterations in oxylipin metabolism as characteristics of breast cancer patients. We compared the ultra-high-performance liquid chromatography-mass spectrometry (UPLC-MS/MS) oxylipin profile signatures in the blood plasma of 152 healthy volunteers (HC) and 169 patients with different stages of breast cancer (BC). To integrate lipidomics, transcriptomics, and genomics data, we analyzed a transcriptome of 10 open database datasets obtained from tissues and blood cells of BC patients and SNP data for 33 genes related to oxylipin metabolism. We identified 18 oxylipins, metabolites of omega-3 or omega-6 polyunsaturated fatty acids, that were differentially expressed between BCvsHC patients, including anandamide, prostaglandins and hydroxydocosahexaenoic acids. DEGs analysis of tissue and blood samples from BC patients revealed that 19 genes for oxylipin biosynthesis change their expression level, with CYP2C19, PTGS2, HPGD, and FAAH included in the list of DEGs in the analysis of transcriptomes and the list of SNPs associated with BC. Results allow us to suppose that oxylipin signatures reflect the organism’s level of response to the disease. Our data regarding changes in oxylipins at the system level show that oxylipin profiles can be used to evaluate the early stages of breast cancer. Full article

(This article belongs to the Special Issue Advanced Breast Cancer: From Biology to Cure)

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25 pages, 4791 KiB

Open AccessArticle

Reduction of Metastasis via Epigenetic Modulation in a Murine Model of Metastatic Triple Negative Breast Cancer (TNBC)

by Jessica L. S. Zylla, Mariah M. Hoffman, Simona Plesselova, Somshuvra Bhattacharya, Kristin Calar, Yohannes Afeworki, Pilar de la Puente, Etienne Z. Gnimpieba, W. Keith Miskimins and Shanta M. Messerli

Cancers 2022, 14(7), 1753; https://doi.org/10.3390/cancers14071753 - 30 Mar 2022

Cited by 10 | Viewed by 3174

Abstract

This study investigates the effects of a dual selective Class I histone deacetylase (HDAC)/lysine-specific histone demethylase 1A (LSD1) inhibitor known as 4SC-202 (Domatinostat) on tumor growth and metastasis in a highly metastatic murine model of Triple Negative Breast Cancer (TNBC). 4SC-202 is cytotoxic [...] Read more.

This study investigates the effects of a dual selective Class I histone deacetylase (HDAC)/lysine-specific histone demethylase 1A (LSD1) inhibitor known as 4SC-202 (Domatinostat) on tumor growth and metastasis in a highly metastatic murine model of Triple Negative Breast Cancer (TNBC). 4SC-202 is cytotoxic and cytostatic to the TNBC murine cell line 4T1 and the human TNBC cell line MDA-MB-231; the drug does not kill the normal breast epithelial cell line MCF10A. Furthermore, 4SC-202 reduces cancer cell migration. In vivo studies conducted in the syngeneic 4T1 model, which closely mimics human TNBC in terms of sites of metastasis, reveal reduced tumor burden and lung metastasis. The mechanism of action of 4SC-202 may involve effects on cancer stem cells (CSC) which can self-renew and form metastatic lesions. Approximately 5% of the total 4T1 cell population grown in three-dimensional scaffolds had a distinct CD44^high/CD24^low CSC profile which decreased after treatment. Bulk transcriptome (RNA) sequencing analyses of 4T1 tumors reveal changes in metastasis-related pathways in 4SC-202-treated tumors, including changes to expression levels of genes implicated in cell migration and cell motility. In summary, 4SC-202 treatment of tumors from a highly metastatic murine model of TNBC reduces metastasis and warrants further preclinical studies. Full article

(This article belongs to the Special Issue Advanced Breast Cancer: From Biology to Cure)

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12 pages, 1578 KiB

Open AccessArticle

Diagnostic Accuracy of Contrast-Enhanced, Spectral Mammography (CESM) and 3T Magnetic Resonance Compared to Full-Field Digital Mammography plus Ultrasound in Breast Lesions: Results of a (Pilot) Open-Label, Single-Centre Prospective Study

by Francesca Romana Ferranti, Federica Vasselli, Maddalena Barba, Francesca Sperati, Irene Terrenato, Franco Graziano, Patrizia Vici, Claudio Botti and Antonello Vidiri

Cancers 2022, 14(5), 1351; https://doi.org/10.3390/cancers14051351 - 7 Mar 2022

Cited by 6 | Viewed by 5436

Abstract

Introduction: To assess the diagnostic accuracy of CESM and 3T MRI compared to full-field digital mammography (FFDM), plus US, in the evaluation of advanced breast lesions. Materials and Methods: Consenting women with suspicious findings underwent FFDM, US, CESM and 3T MRI. Breast lesions [...] Read more.

Introduction: To assess the diagnostic accuracy of CESM and 3T MRI compared to full-field digital mammography (FFDM), plus US, in the evaluation of advanced breast lesions. Materials and Methods: Consenting women with suspicious findings underwent FFDM, US, CESM and 3T MRI. Breast lesions were histologically assessed, with histology being the gold standard. Two experienced breast radiologists, blinded to cancer status, read the images. Diagnostic accuracy of (1) CESM as an adjunct to FFDM and US, and (2) 3T MRI as an adjunct to CESM compared to FFDM and US, was assessed. Measures of accuracy were sensitivity (Se), specificity (Sp), positive predictive value (PPV) and negative predictive value (NPV). Results: There were 118 patients included along with 142 histologically characterized lesions. K agreement values were 0.69, 0.68, 0.63 and 0.56 for concordance between the gold standard and FFDM, FFDM + US, CESM and MRI, respectively (p < 0.001, for all). K concordance for CESM was 0.81 with FFDM + US and 0.73 with MRI (p value < 0.001 for all). Conclusions: CESM may represent a valuable alternative and/or an integrating technique to MRI in the evaluation of breast cancer patients. Full article

(This article belongs to the Special Issue Advanced Breast Cancer: From Biology to Cure)

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18 pages, 5438 KiB

Open AccessArticle

BHMPS Inhibits Breast Cancer Migration and Invasion by Disrupting Rab27a-Mediated EGFR and Fibronectin Secretion

by Jeong-In Park, Kyung-Hee Song, Seong-Mook Kang, Jeeyong Lee, Seong-Jun Cho, Hyun Kyung Choi, Jiyeon Ahn, Jong-Kuk Park, Jaesung Kim, Sang-Gu Hwang, Dae-Seog Lim, Joon Kim, Seung-Youn Jung and Jie-Young Song

Cancers 2022, 14(2), 373; https://doi.org/10.3390/cancers14020373 - 12 Jan 2022

Cited by 6 | Viewed by 2347

Abstract

Our previous work demonstrated that (E)-N-benzyl-6-(2-(3, 4-dihydroxybenzylidene) hydrazinyl)-N-methylpyridine-3-sulfonamide (BHMPS), a novel synthetic inhibitor of Rab27aSlp(s) interaction, suppresses tumor cell invasion and metastasis. Here, we aimed to further investigate the mechanisms of action and biological significance of BHMPS. [...] Read more.

Our previous work demonstrated that (E)-N-benzyl-6-(2-(3, 4-dihydroxybenzylidene) hydrazinyl)-N-methylpyridine-3-sulfonamide (BHMPS), a novel synthetic inhibitor of Rab27aSlp(s) interaction, suppresses tumor cell invasion and metastasis. Here, we aimed to further investigate the mechanisms of action and biological significance of BHMPS. BHMPS decreased the expression of epithelial-mesenchymal transition transcription factors through inhibition of focal adhesion kinase and c-Jun N-terminal kinase activation, thereby reducing the migration and invasion of breast cancer. Additionally, knockdown of Rab27a inhibited tumor migration, with changes in related signaling molecules, whereas overexpression of Rab27a reversed this phenomenon. BHMPS effectively prevented the interaction of Rab27a and its effector Slp4, which was verified by co-localization, immunoprecipitation, and in situ proximity ligation assays. BHMPS decreased the secretion of epidermal growth factor receptor and fibronectin by interfering with vesicle trafficking, as indicated by increased perinuclear accumulation of CD63-positive vesicles. Moreover, administration of BHMPS suppressed tumor growth in Rab27a-overexpressing MDA-MB-231 xenograft mice. These findings suggest that BHMPS may be a promising candidate for attenuating tumor migration and invasion by blocking Rab27a-mediated exocytosis. Full article

(This article belongs to the Special Issue Advanced Breast Cancer: From Biology to Cure)

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11 pages, 832 KiB

Open AccessArticle

Assessment of Resistance Mechanisms and Clinical Implications in Patients with KRAS Mutated-Metastatic Breast Cancer and Resistance to CDK4/6 Inhibitors

by Lucrezia Raimondi, Filippo Maria Raimondi, Marta Pietranera, Arianna Di Rocco, Laura Di Benedetto, Evelina Miele, Rachele Lazzeroni, Giuseppe Cimino and Gian Paolo Spinelli

Cancers 2021, 13(8), 1928; https://doi.org/10.3390/cancers13081928 - 16 Apr 2021

Cited by 16 | Viewed by 2959

Abstract

Despite therapeutic improvements, resistance to palbociclib is a growing clinical challenge which is poorly understood. This study was conducted in order to understand the molecular mechanisms of resistance to palbociclib, and to identify biomarkers to predict who will take advantage from cyclin-dependent kinase [...] Read more.

Despite therapeutic improvements, resistance to palbociclib is a growing clinical challenge which is poorly understood. This study was conducted in order to understand the molecular mechanisms of resistance to palbociclib, and to identify biomarkers to predict who will take advantage from cyclin-dependent kinase 4/6 inhibitors (CDK4/6i). A total of about a thousand blood samples were collected from 106 patients with hormone receptor positive (HR+) human epidermal growth factor receptor 2 (HER2) negative metastatic breast cancer who received palbociclib in combination with fulvestrant as the first-line metastatic therapy enrolled in this study. The genotyping of their plasma cell-free DNA was studied, including serial plasma samples. Collectively, our findings identify the appearance of KRAS mutations leading to palbociclib resistance acquisition within 6 months, and provide critical information for the prediction of therapeutic responses in metastatic breast cancer. By monitoring KRAS status through liquid biopsy, we could predict who will take advantage from the combination of palbociclib and fulvestrant, offering highly-individualized treatment plans, thus ensuring the best patient quality of life. Full article

(This article belongs to the Special Issue Advanced Breast Cancer: From Biology to Cure)

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18 pages, 3463 KiB

Open AccessArticle

Ginsenoside Rh1 Induces MCF-7 Cell Apoptosis and Autophagic Cell Death through ROS-Mediated Akt Signaling

by Diem Thi Ngoc Huynh, Yujin Jin, Chang-Seon Myung and Kyung-Sun Heo

Cancers 2021, 13(8), 1892; https://doi.org/10.3390/cancers13081892 - 15 Apr 2021

Cited by 36 | Viewed by 4344

Abstract

Breast cancer (BC) is the leading cause of cancer-related deaths among women worldwide. Ginsenosides exhibit anticancer activity against various cancer cells. However, the effects of ginsenoside Rh1 on BC and the underlying mechanisms remain unknown. Here, we investigated the anticancer effects of Rh1 [...] Read more.

Breast cancer (BC) is the leading cause of cancer-related deaths among women worldwide. Ginsenosides exhibit anticancer activity against various cancer cells. However, the effects of ginsenoside Rh1 on BC and the underlying mechanisms remain unknown. Here, we investigated the anticancer effects of Rh1 on human BC MCF-7 and HCC1428 cells and the underlying signaling pathways. The anticancer effects of Rh1 in vitro were evaluated using sulforhodamine B (SRB), 3-(4, 5-dimethylthiazole-2-yl)-2, 5-diphenyltetrazolium bromide (MTT), clonogenic assay, propidium iodide (PI)/Hoechst staining, Western blotting, flow cytometry, and immunofluorescence analysis. The in vivo effects of Rh1 were determined using a xenograft model via hematoxylin and eosin and the immunohistochemistry staining of tumor tissues. We found that Rh1 exerted cytotoxicity in the cells by increasing cell apoptosis, autophagy, and cell cycle arrest. These effects were further enhanced by a phosphatidylinositol 3-kinase (PI3K) inhibitor but were rescued by the inhibition of reactive oxygen species (ROS). Moreover, enhanced ROS generation by Rh1 inhibited the activation of the PI3K/Akt pathway. Consistently, Rh1 treatment significantly reduced tumor growth in vivo and increased the ROS production and protein expression of LC3B and cleaved caspase-3 but decreased the phosphorylation of Akt and retinoblastoma (Rb) in tumor tissues. Taken together, Rh1 exerted a potential anticancer effect on BC cells by inducing cell cycle arrest, apoptosis, and autophagy via inhibition of the ROS-mediated PI3K/Akt pathway. Full article

(This article belongs to the Special Issue Advanced Breast Cancer: From Biology to Cure)

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Review

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21 pages, 692 KiB

Open AccessReview

PI3K Inhibitors in Advanced Breast Cancer: The Past, The Present, New Challenges and Future Perspectives

by Paola Fuso, Margherita Muratore, Tatiana D’Angelo, Ida Paris, Luisa Carbognin, Giordana Tiberi, Francesco Pavese, Simona Duranti, Armando Orlandi, Giampaolo Tortora, Giovanni Scambia and Alessandra Fabi

Cancers 2022, 14(9), 2161; https://doi.org/10.3390/cancers14092161 - 26 Apr 2022

Cited by 19 | Viewed by 4715

Abstract

Breast cancer is the leading cause of death in the female population and despite significant efforts made in diagnostic approaches and treatment strategies adopted for advanced breast cancer, the disease still remains incurable. Therefore, development of more effective systemic treatments constitutes a crucial [...] Read more.

Breast cancer is the leading cause of death in the female population and despite significant efforts made in diagnostic approaches and treatment strategies adopted for advanced breast cancer, the disease still remains incurable. Therefore, development of more effective systemic treatments constitutes a crucial need. Recently, several clinical trials were performed to find innovative predictive biomarkers and to improve the outcome of metastatic breast cancer through innovative therapeutic algorithms. In the pathogenesis of breast cancer, the phosphatidylinositol 3-kinase (PI3K)-protein kinase B (PKB/AKT)-mammalian target of rapamycin (mTOR) axis is a key regulator of cell proliferation, growth, survival, metabolism, and motility, making it an interest and therapeutic target. Nevertheless, the PI3K/AKT/mTOR cascade includes a complex network of biological events, needing more sophisticated approaches for their use in cancer treatment. In this review, we described the rationale for targeting the PI3K pathway, the development of PI3K inhibitors and the future treatment directions of different breast cancer subtypes in the metastatic setting. Full article

(This article belongs to the Special Issue Advanced Breast Cancer: From Biology to Cure)

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17 pages, 4051 KiB

Open AccessReview

Radiotherapy for HER 2 Positive Brain Metastases: Urgent Need for a Paradigm Shift

by Edy Ippolito, Sonia Silipigni, Paolo Matteucci, Carlo Greco, Sofia Carrafiello, Vincenzo Palumbo, Claudia Tacconi, Claudia Talocco, Michele Fiore, Rolando Maria D’Angelillo and Sara Ramella

Cancers 2022, 14(6), 1514; https://doi.org/10.3390/cancers14061514 - 15 Mar 2022

Cited by 8 | Viewed by 3404

Abstract

Brain metastases (BMs) are common among patients affected by HER2+ metastatic breast cancer (>30%). The management of BMs is usually multimodal, including surgery, radiotherapy, systemic therapy and palliative care. Standard brain radiotherapy (RT) includes the use of stereotactic radiotherapy (SRT) for limited disease [...] Read more.

Brain metastases (BMs) are common among patients affected by HER2+ metastatic breast cancer (>30%). The management of BMs is usually multimodal, including surgery, radiotherapy, systemic therapy and palliative care. Standard brain radiotherapy (RT) includes the use of stereotactic radiotherapy (SRT) for limited disease and whole brain radiotherapy (WBRT) for extensive disease. The latter is an effective palliative treatment but has a reduced effect on brain local control and BM overall survival, as it is also associated with severe neurocognitive sequelae. Recent advances both in radiation therapy and systemic treatment may change the paradigm in this subset of patients who can experience long survival notwithstanding BMs. In fact, in recent studies, SRT for multiple BM sites (>4) has shown similar efficacy when compared to irradiation of a limited number of lesions (one to three) without increasing toxicity. These findings, in addition to the introduction of new drugs with recognized intracranial activity, may further limit the use of WBRT in favor of SRT, which should be employed for treatment of both multiple-site BMs and for oligo-progressive brain disease. This review summarizes the supporting literature and highlights the need for optimizing combinations of the available treatments in this setting, with a particular focus on radiation therapy. Full article

(This article belongs to the Special Issue Advanced Breast Cancer: From Biology to Cure)

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17 pages, 818 KiB

Open AccessReview

Breast Cancer Drug Approvals Issued by EMA: A Review of Clinical Trials

by Simona Duranti, Alessandra Fabi, Marco Filetti, Rosa Falcone, Pasquale Lombardi, Gennaro Daniele, Gianluca Franceschini, Luisa Carbognin, Antonella Palazzo, Giorgia Garganese, Ida Paris, Giovanni Scambia and Antonella Pietragalla

Cancers 2021, 13(20), 5198; https://doi.org/10.3390/cancers13205198 - 16 Oct 2021

Cited by 10 | Viewed by 3048

Abstract

Breast cancer represents the first cause of cancer worldwide and the leading cause of cancer mortality for women. Therefore, new therapies are needed to improve the prognosis of women diagnosed with this disease. In this review, we summarize the new drug indications for [...] Read more.

Breast cancer represents the first cause of cancer worldwide and the leading cause of cancer mortality for women. Therefore, new therapies are needed to improve the prognosis of women diagnosed with this disease. In this review, we summarize the new drug indications for the treatment of breast cancer approved by European Medicines Agency between January 2015 and June 2021. In particular, we analyzed the clinical trials results leading to approvals and their update (when available), according to setting (localized and locally advanced or metastatic) and clinical features (hormone receptor positive, HER2 positive, triple negative, BRCA 1/2 mutation). The aim of this paper is to describe the clinical benefit obtained with the new indications. Full article

(This article belongs to the Special Issue Advanced Breast Cancer: From Biology to Cure)

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30 pages, 507 KiB

Open AccessEditor’s ChoiceReview

Breast Cancer—Epidemiology, Risk Factors, Classification, Prognostic Markers, and Current Treatment Strategies—An Updated Review

by Sergiusz Łukasiewicz, Marcin Czeczelewski, Alicja Forma, Jacek Baj, Robert Sitarz and Andrzej Stanisławek

Cancers 2021, 13(17), 4287; https://doi.org/10.3390/cancers13174287 - 25 Aug 2021

Cited by 693 | Viewed by 73818

Abstract

Breast cancer (BC) is the most frequently diagnosed cancer in women worldwide with more than 2 million new cases in 2020. Its incidence and death rates have increased over the last three decades due to the change in risk factor profiles, better cancer [...] Read more.

Breast cancer (BC) is the most frequently diagnosed cancer in women worldwide with more than 2 million new cases in 2020. Its incidence and death rates have increased over the last three decades due to the change in risk factor profiles, better cancer registration, and cancer detection. The number of risk factors of BC is significant and includes both the modifiable factors and non-modifiable factors. Currently, about 80% of patients with BC are individuals aged >50. Survival depends on both stage and molecular subtype. Invasive BCs comprise wide spectrum tumors that show a variation concerning their clinical presentation, behavior, and morphology. Based on mRNA gene expression levels, BC can be divided into molecular subtypes (Luminal A, Luminal B, HER2-enriched, and basal-like). The molecular subtypes provide insights into new treatment strategies and patient stratifications that impact the management of BC patients. The eighth edition of TNM classification outlines a new staging system for BC that, in addition to anatomical features, acknowledges biological factors. Treatment of breast cancer is complex and involves a combination of different modalities including surgery, radiotherapy, chemotherapy, hormonal therapy, or biological therapies delivered in diverse sequences. Full article

(This article belongs to the Special Issue Advanced Breast Cancer: From Biology to Cure)

20 pages, 1086 KiB

Open AccessReview

CDK4/6 Inhibitor Treatments in Patients with Hormone Receptor Positive, Her2 Negative Advanced Breast Cancer: Potential Molecular Mechanisms, Clinical Implications and Future Perspectives

by Michela Roberto, Antonio Astone, Andrea Botticelli, Luisa Carbognin, Alessandra Cassano, Giuliana D’Auria, Agnese Fabbri, Alessandra Fabi, Teresa Gamucci, Eriseld Krasniqi, Mauro Minelli, Armando Orlandi, Francesco Pantano, Ida Paris, Laura Pizzuti, Ilaria Portarena, Nello Salesi, Simone Scagnoli, Paola Scavina, Giuseppe Tonini, Patrizia Vici and Paolo Marchetti Show full author list Hide full author list

Cancers 2021, 13(2), 332; https://doi.org/10.3390/cancers13020332 - 18 Jan 2021

Cited by 44 | Viewed by 8022

Abstract

Hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer is the most common breast cancer subtype, and endocrine therapy (ET) remains its therapeutic backbone. Although anti-estrogen therapies are usually effective initially, approximately 50% of HR+ patients develop resistance to ET [...] Read more.

Hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer is the most common breast cancer subtype, and endocrine therapy (ET) remains its therapeutic backbone. Although anti-estrogen therapies are usually effective initially, approximately 50% of HR+ patients develop resistance to ET within their lifetime, ultimately leading to disease recurrence and limited clinical benefit. The recent addition of cyclin-dependent kinase 4 (CDK4) and CDK6 inhibitors (palbociclib, ribociclib, abemaciclib) to ET have remarkably improved the outcome of patients with HR+ advanced breast cancer (ABC) compared with anti-estrogens alone, by targeting the cell-cycle machinery and overcoming some aspects of endocrine resistance. However, which patients are the better candidates for these drugs, which are the main characteristics for a better selection of patients or if there are predictive biomarkers of response, is still unknown. In this review we reported the mechanism of action of CDK4/6 inhibitors as well as their potential mechanism of resistance, their implications in clinical practice and the forthcoming strategies to enhance their efficacy in improving survival and quality of life of patients affected with HR+, HER2−, ABC. Full article

(This article belongs to the Special Issue Advanced Breast Cancer: From Biology to Cure)

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