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Molecular Basis and Advances of Targeted Therapy for Breast Cancer

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: 30 May 2024 | Viewed by 9436

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Dr. Nicoletta Cordani

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Guest Editor

School of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy
Interests: cancer; resistance to TK or CDK inhibitors; epigenetics; NGSseq
Special Issues, Collections and Topics in MDPI journals

Dr. Monica Iorfida

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Guest Editor

Division of Medical Senology, IEO, European Institute of Oncology IRCCS, 20141 Milan, Italy
Interests: cancer; breast cancer; triple-negative breast cancer

Special Issue Information

Dear Colleagues,

This Special Issue focuses on translational science in the hopes of shedding light on research focused on “Molecular Basis and Advances of Targeted Therapy for Breast Cancer” and the therapy on breast cancer and overcoming breast cancer therapy resistance. Breast cancer (BC) is the most frequent cancer and the second cause of death by cancer in women worldwide.

The BC molecular subtype can determine the personalized therapeutic approach, e.g., targeted treatments such as endocrine therapy for HR+ BC or anti-HER2 therapy for HER2+ BC. The major challenge in BC treatment is finding active therapies to treat triple-negative breast cancer (TNBC) patients since conventional targeted therapies cannot be administered for this specific BC subtype, which has the worst survival outcomes. the mechanisms underlying drug resistance are a good strategy to develop novel treatments for BC. Acquired drug resistance is one of the main restrictions to the efficacious treatment of cancer. The mTOR/PI3K/Akt pathway is involved in the mechanism of resistance in all BC molecular subtypes, but many data show that resistance results from drug exclusion, drug metabolism, and modification of the drug target due to mutation or overexpression. Depending on the therapy, one or more genetic or epigenetic modulations are required to confer resistance to treatment. The editors welcome submissions from researchers involved in basic cancer research as well as clinical research. The articles should demonstrate a clear understanding of tumor cells and treatment strategies specific to the tumor types and clarify the ways that lead to therapy resistance from cell lines to clinical trials. Reviews and original papers are both welcome.

Dr. Nicoletta Cordani
Dr. Monica Iorfida
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Published Papers (8 papers)

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Research

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19 pages, 13610 KiB

Open AccessArticle

MerTK Drives Proliferation and Metastatic Potential in Triple-Negative Breast Cancer

by Mari Iida, Bridget E. Crossman, Kourtney L. Kostecki, Christine E. Glitchev, Carlene A. Kranjac, Madisen T. Crow, Jillian M. Adams, Peng Liu, Irene Ong, David T. Yang, Irene Kang, Ravi Salgia and Deric L. Wheeler

Int. J. Mol. Sci. 2024, 25(10), 5109; https://doi.org/10.3390/ijms25105109 - 8 May 2024

Viewed by 274

Abstract

Triple-negative breast cancer (TNBC) is characterized by the absence of the estrogen receptor, progesterone receptor, and receptor tyrosine kinase HER2 expression. Due to the limited number of FDA-approved targeted therapies for TNBC, there is an ongoing need to understand the molecular underpinnings of TNBC for the development of novel combinatorial treatment strategies. This study evaluated the role of the MerTK receptor tyrosine kinase on proliferation and invasion/metastatic potential in TNBC. Immunohistochemical analysis demonstrated MerTK expression in 58% of patient-derived TNBC xenografts. The stable overexpression of MerTK in human TNBC cell lines induced an increase in proliferation rates, robust in vivo tumor growth, heightened migration/invasion potential, and enhanced lung metastases. NanoString nCounter analysis of MerTK-overexpressing SUM102 cells (SUM102-MerTK) revealed upregulation of several signaling pathways, which ultimately drive cell cycle progression, reduce apoptosis, and enhance cell survival. Proteomic profiling indicated increased endoglin (ENG) production in SUM102-MerTK clones, suggesting that MerTK creates a conducive environment for increased proliferative and metastatic activity via elevated ENG expression. To determine ENG’s role in increasing proliferation and/or metastatic potential, we knocked out ENG in a SUM102-MerTK clone with CRISPR technology. Although this ENG knockout clone exhibited similar in vivo growth to the parental SUM102-MerTK clone, lung metastasis numbers were significantly decreased ~4-fold, indicating that MerTK enhances invasion and metastasis through ENG. Our data suggest that MerTK regulates a unique proliferative signature in TNBC, promoting robust tumor growth and increased metastatic potential through ENG upregulation. Targeting MerTK and ENG simultaneously may provide a novel therapeutic approach for TNBC patients. Full article

(This article belongs to the Special Issue Molecular Basis and Advances of Targeted Therapy for Breast Cancer)

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17 pages, 5036 KiB

Open AccessArticle

B7-H3 Expression in Breast Cancer and Brain Metastasis

by Vaibhavi Joshi, Kate Beecher, Malcolm Lim, Andrew Stacey, Yufan Feng, Parmjit S. Jat, Pascal H. G. Duijf, Peter T. Simpson, Sunil R. Lakhani and Amy E. McCart Reed

Int. J. Mol. Sci. 2024, 25(7), 3976; https://doi.org/10.3390/ijms25073976 - 3 Apr 2024

Viewed by 791

Abstract

Brain metastasis is a significant challenge for some breast cancer patients, marked by its aggressive nature, limited treatment options, and poor clinical outcomes. Immunotherapies have emerged as a promising avenue for brain metastasis treatment. B7-H3 (CD276) is an immune checkpoint molecule involved in T cell suppression, which is associated with poor survival in cancer patients. Given the increasing number of clinical trials using B7-H3 targeting CAR T cell therapies, we examined B7-H3 expression across breast cancer subtypes and in breast cancer brain metastases to assess its potential as an interventional target. B7-H3 expression was investigated using immunohistochemistry on tissue microarrays of three clinical cohorts: (i) unselected primary breast cancers (n = 347); (ii) brain metastatic breast cancers (n = 61) and breast cancer brain metastases (n = 80, including a subset of 53 patient-matched breast and brain metastasis cases); and (iii) mixed brain metastases from a range of primary tumours (n = 137). In primary breast cancers, B7-H3 expression significantly correlated with higher tumour grades and aggressive breast cancer subtypes, as well as poorer 5-year survival outcomes. Subcellular localisation of B7-H3 impacted breast cancer-specific survival, with cytoplasmic staining also correlating with a poorer outcome. Its expression was frequently detected in brain metastases from breast cancers, with up to 90% expressing B7-H3. However, not all brain metastases showed high levels of expression, with those from colorectal and renal tumours showing a low frequency of B7-H3 expression (0/14 and 2/16, respectively). The prevalence of B7-H3 expression in breast cancers and breast cancer brain metastases indicates potential opportunities for B7-H3 targeted therapies in breast cancer management. Full article

(This article belongs to the Special Issue Molecular Basis and Advances of Targeted Therapy for Breast Cancer)

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14 pages, 3408 KiB

Open AccessArticle

Real-World Data and Clinical Implications of Next-Generation Sequencing (NGS)-Based Analysis in Metastatic Breast Cancer Patients

by Fabio Canino, Antonio Tornincasa, Stefania Bettelli, Samantha Manfredini, Monica Barbolini, Luca Moscetti, Claudia Omarini, Angela Toss, Fabio Tamburrano, Giuseppina Antonelli, Federica Baglio, Lorenzo Belluzzi, Giulio Martinelli, Salvatore Natalizio, Ornella Ponzoni, Massimo Dominici and Federico Piacentini

Int. J. Mol. Sci. 2024, 25(5), 2490; https://doi.org/10.3390/ijms25052490 - 20 Feb 2024

Viewed by 1043

Abstract

Over the last two decades, the use of Next-Generation Sequencing (NGS) in medical oncology has increased the likelihood of identifying druggable mutations that may be potentially susceptible to targeted treatments. The European Society for Medical Oncology (ESMO) currently does not recommend the use of the NGS test to determine the therapeutic course of patients with metastatic breast cancer (mBC) in daily clinical practice. However, the aim of this work is to evaluate the potential contribution of the NGS test in selecting targeted therapies for patients with mBC. Data were retrospectively collected from 101 patients diagnosed with metastatic breast cancer and treated at the Modena Cancer Center between January 2015 and April 2022. A NGS test was performed on the tumor tissue of each patient at the Laboratory of Molecular Pathology of the University Hospital of Modena. This study analyzed the clinical–pathological characteristics and mutational profile of the population using NGS tests, with a focus on actionable mutations that could be targeted in advanced stages of clinical development. The indicator of this study was to quantify the actionable mutations that resulted in a change of cancer treatment. In total, 101 patients with metastatic breast cancer were analyzed, including 86 with luminal phenotype, 10 who were HER2-positive and 5 who were triple-negative. Median age was 52 years. NGS analysis was conducted on 47 samples of primary breast cancer, 52 on metastatic sites of disease and 2 on liquid biopsies. A total of 85 gene mutations were found. The most common mutations were identified in the PIK3CA (47%), FGFR (19%) and ERBB2 genes (12%), and to a lesser extent in other genes. Of the 61 patients with pathogenic mutations, 46 (75%) had at least one actionable mutation. Of these, nine received treatment with a molecular target drug: eight patients with a mutation of the PIK3CA gene were treated with alpelisib and fulvestrant; one patient with FGFR1/2 amplifications received TAS120. Median PFS for these patients was 3.8 months. The study results show that using the NGS test on cancer tissue of metastatic breast cancer could influence the therapeutic choices, considering the small sample size and limited follow-up. About 9% of the study population had their therapy modified based on the results of NGS. The growing number of detectable mutations and increased accessibility of the test may lead to a greater number of potential therapeutic implications for the NGS assay. Perspectives suggest that NGS analysis can be implemented in daily clinical practice, particularly in contexts where a Molecular Tumor Board (MTB) is active. Full article

(This article belongs to the Special Issue Molecular Basis and Advances of Targeted Therapy for Breast Cancer)

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17 pages, 2940 KiB

Open AccessArticle

TWIST1 Upregulation Is a Potential Target for Reversing Resistance to the CDK4/6 Inhibitor in Metastatic Luminal Breast Cancer Cells

by Nicoletta Cordani, Luca Mologni, Rocco Piazza, Pietro Tettamanti, Viola Cogliati, Mario Mauri, Matteo Villa, Federica Malighetti, Camillo Di Bella, Marta Jaconi, Maria Grazia Cerrito, Guido Cavaletti, Marialuisa Lavitrano and Marina Elena Cazzaniga

Int. J. Mol. Sci. 2023, 24(22), 16294; https://doi.org/10.3390/ijms242216294 - 14 Nov 2023

Cited by 4 | Viewed by 1207

Abstract

Cyclin-dependent kinase (CDK) 4/6 inhibitors have significantly improved progression-free survival in hormone-receptor-positive (HR+), human-epidermal-growth-factor-receptor-type-2-negative (HER2−) metastatic luminal breast cancer (mLBC). Several studies have shown that in patients with endocrine-sensitive or endocrine-resistant LBC, the addition of CDK4/6 inhibitors to endocrine therapy significantly prolongs progression-free survival. However, the percentage of patients who are unresponsive or refractory to these therapies is as high as 40%, and no reliable and reproducible biomarkers have been validated to select a priori responders or refractory patients. The selection of mutant clones in the target oncoprotein is the main cause of resistance. Other mechanisms such as oncogene amplification/overexpression or mutations in other pathways have been described in several models. In this study, we focused on palbociclib, a selective CDK4/6 inhibitor. We generated a human MCF-7 luminal breast cancer cell line that was able to survive and proliferate at different concentrations of palbociclib and also showed cross-resistance to abemaciclib. The resistant cell line was characterized via RNA sequencing and was found to strongly activate the epithelial-to-mesenchymal transition. Among the top deregulated genes, we found a dramatic downregulation of the CDK4 inhibitor CDKN2B and an upregulation of the TWIST1 transcription factor. TWIST1 was further validated as a target for the reversal of palbociclib resistance. This study provides new relevant information about the mechanisms of resistance to CDK4/6 inhibitors and suggests potential new markers for patients’ follow-up care during treatment. Full article

(This article belongs to the Special Issue Molecular Basis and Advances of Targeted Therapy for Breast Cancer)

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15 pages, 3742 KiB

Open AccessArticle

Evaluating [¹⁸F]FDG and [¹⁸F]FLT Radiotracers as Biomarkers of Response for Combined Therapy Outcome in Triple-Negative and Estrogen-Receptor-Positive Breast Cancer Models

by Paolo Rainone, Silvia Valtorta, Chiara Villa, Sergio Todde, Massimiliano Cadamuro, Gloria Bertoli, Donatella Conconi, Marialuisa Lavitrano and Rosa Maria Moresco

Int. J. Mol. Sci. 2023, 24(18), 14124; https://doi.org/10.3390/ijms241814124 - 15 Sep 2023

Cited by 1 | Viewed by 1107

Abstract

Breast cancer (BC) is the most frequent cancer and the second leading cause of death in women. A typical feature of BC cells is the metabolic shift toward increased glycolysis, which has become an interesting therapeutic target for metabolic drugs such as metformin (MET). Recently, the administration of the antihypertensive syrosingopine (SYRO) in combination with MET has shown a synergistic effect toward a variety of cancers. However, a fundamental need remains, which is the development of in vivo biomarkers that are able to detect early clinical response. In this study, we exploited a triple-negative murine BC cell line (4T1) and a metastatic ER+ murine BC cell line (TS/A) in order to investigate, in vivo, the early response to treatment, based on MET and/or SYRO administration, evaluating [¹⁸F]FDG and [¹⁸F]FLT as potential biomarkers via PET/CT. The study provides evidence that SYRO plus MET has a synergistic effect on tumor growth inhibition in both 4T1 and TS/A experimental models and has showed the highest efficacy on the TNBC xenograft mice (4T1) via the expression reduction in the lactate transporter MCT4 and in the epithelial–mesenchymal transition biomarker Snail, promoting its potential application in therapy settings. In addition, the selective reduction in the [¹⁸F]FLT tumor uptake (at 7 dd), observed in the SYRO plus MET treated mice in comparison with the vehicle group, suggests that this radiotracer could be potentially used as a biomarker for the early detection of therapy response, in both evaluated xenografts models. Full article

(This article belongs to the Special Issue Molecular Basis and Advances of Targeted Therapy for Breast Cancer)

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20 pages, 5165 KiB

Open AccessArticle

Single-Cell Transcriptional and Epigenetic Profiles of Male Breast Cancer Nominate Salient Cancer-Specific Enhancers

by Hyunsoo Kim, Kamila Wisniewska, Matthew J. Regner, Aatish Thennavan, Philip M. Spanheimer and Hector L. Franco

Int. J. Mol. Sci. 2023, 24(17), 13053; https://doi.org/10.3390/ijms241713053 - 22 Aug 2023

Viewed by 1527

Abstract

Male breast cancer represents about 1% of all breast cancer diagnoses and, although there are some similarities between male and female breast cancer, the paucity of data available on male breast cancer makes it difficult to establish targeted therapies. To date, most male breast cancers (MBCs) are treated according to protocols established for female breast cancer (FBC). Thus, defining the transcriptional and epigenetic landscape of MBC with improved resolution is critical for developing better avenues for therapeutic intervention. In this study, we present matched transcriptional (scRNA-seq) and epigenetic (scATAC-seq) profiles at single-cell resolution of two treatment naïve MBC tumors processed immediately after surgical resection. These data enable the detection of differentially expressed genes between male and female breast tumors across immune, stromal, and malignant cell types, to highlight several genes that may have therapeutic implications. Notably, MYC target genes and mTORC1 signaling genes were significantly upregulated in the malignant cells of MBC compared to the female counterparts. To understand how the regulatory landscape of MBC gives rise to these male-specific gene expression patterns, we leveraged the scATAC-seq data to systematically link changes in chromatin accessibility to changes in gene expression within each cell type. We observed cancer-specific rewiring of several salient enhancers and posit that these enhancers have a higher regulatory load than lineage-specific enhancers. We highlight two examples of previously unannotated cancer-cell-specific enhancers of ANXA2 and PRDX4 gene expression and show evidence for super-enhancer regulation of LAMB3 and CD47 in male breast cancer cells. Overall, this dataset annotates clinically relevant regulatory networks in male breast tumors, providing a useful resource that expands our current understanding of the gene expression programs that underlie the biology of MBC. Full article

(This article belongs to the Special Issue Molecular Basis and Advances of Targeted Therapy for Breast Cancer)

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10 pages, 1236 KiB

Open AccessArticle

Calcium-Sensing Receptor Expression in Breast Cancer

by Iva Busic-Pavlek, Ivo Dumic-Cule, Lucija Kovacevic, Milan Milosevic, Petra Delimar, Lea Korsa, Zlatko Marusic and Maja Prutki

Int. J. Mol. Sci. 2023, 24(14), 11678; https://doi.org/10.3390/ijms241411678 - 20 Jul 2023

Cited by 1 | Viewed by 1040

Abstract

The calcium-sensing receptor (CaSR) plays a crucial role in maintaining the balance of calcium in the body. Altered signaling through the CaSR has been linked to the development of various tumors, such as colorectal and breast tumors. This retrospective study enrolled 79 patients who underwent surgical removal of invasive breast carcinoma of no special type (NST) to explore the expression of the CaSR in breast cancer. The patients were categorized based on age, tumor size, hormone receptor status, HER2 status, Ki-67 proliferation index, tumor grade, and TNM staging. Immunohistochemistry was conducted on core needle biopsy samples to assess CaSR expression. The results revealed a positive correlation between CaSR expression and tumor size, regardless of the tumor surrogate subtype (p = 0.001). The expression of ER exhibited a negative correlation with CaSR expression (p = 0.033). In contrast, a positive correlation was observed between CaSR expression and the presence of HER2 receptors (p = 0.002). Increased CaSR expression was significantly associated with lymph node involvement and the presence of distant metastasis (p = 0.001 and p = 0.038, respectively). CaSR values were significantly higher in the patients with increased Ki-67 (p = 0.042). Collectively, higher CaSR expression in breast cancer could suggest a poor prognosis and treatment outcome regardless of the breast cancer subtype. Full article

(This article belongs to the Special Issue Molecular Basis and Advances of Targeted Therapy for Breast Cancer)

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Review

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25 pages, 935 KiB

Open AccessReview

Progression after First-Line Cyclin-Dependent Kinase 4/6 Inhibitor Treatment: Analysis of Molecular Mechanisms and Clinical Data

by Federica Villa, Alessandra Crippa, Davide Pelizzoni, Alessandra Ardizzoia, Giulia Scartabellati, Cristina Corbetta, Eleonora Cipriani, Marialuisa Lavitrano and Antonio Ardizzoia

Int. J. Mol. Sci. 2023, 24(19), 14427; https://doi.org/10.3390/ijms241914427 - 22 Sep 2023

Cited by 3 | Viewed by 1660

Abstract

Cyclin-dependent kinase 4/6 inhibitors (CDK4/6iss) are widely used in first-line metastatic breast cancer. For patients with progression under CDK4/6is, there is currently no standard treatment recommended at the category 1 level in international guidelines. The purpose of this article is to review the cellular mechanisms underlying the resistance to CDK4/6is, as well as treatment strategies and the clinical data about the efficacy of subsequent treatments after CDK4/6is-based therapy. In the first part, this review mainly discusses cell-cycle-specific and cell-cycle-non-specific resistance to CDK4/6is, with a focus on early and late progression. In the second part, this review analyzes potential therapeutic approaches and the available clinical data on them: switching to other CDK4/6is, to another single hormonal therapy, to other target therapies (PI3K, mTOR and AKT) and to chemotherapy. Full article

(This article belongs to the Special Issue Molecular Basis and Advances of Targeted Therapy for Breast Cancer)

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