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Cancers
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Genomic Landscape of Breast Cancer: From Primary to Metastasis
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Genomic Landscape of Breast Cancer: From Primary to Metastasis

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Molecular Cancer Biology".

Deadline for manuscript submissions: closed (10 August 2022) | Viewed by 21309

Special Issue Editors

Dr. Athina Giannoudis

E-Mail Website
Guest Editor
Department of Molecular and Clinical Cancer Medicine, The Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Sherrington Building, Ashton Street, Liverpool L69 3GE, UK
Interests: breast cancer; brain metastasis; molecular genetics; pharmacogenetics; drug transporters; micro-RNAs
Dr. Damir Vareslija

E-Mail Website
Co-Guest Editor
Department of Surgery, Royal College of Surgeons in Ireland, Lab 3, 4th Floor, York House, York Street, Dublin 2, Ireland
Interests: breast cancer metastasis; brain metastasis; epigenetics; genomic and transcriptomic alterations
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Breast cancer is the most diagnosed malignancy in women and the second leading cause of cancer death after lung cancer. Although 5–10% of breast cancers are hereditary, linked mainly to BRAC1 and BRAC2 gene mutations, the vast majority occur in women with no family history of breast cancer. These cancers can be due to genetic mutations/alterations that occur because of the aging process and lifestyle in general. In addition, genetic alterations contribute to the development of secondary disease, resistance to therapy, and metastasis. The application of next-generation sequencing technologies has enabled the molecular characterization of primary breast cancers and also demonstrated the complex and diverse molecular landscapes of metastatic disease. To move this information into routine clinical practice, it will be important to further exploit the clinical heterogeneity of primary and metastatic breast cancers. The knowledge of the genomic landscape and its therapeutic implications will allow the use of therapeutic compounds in a more personalized way and the development of investigational, targeted therapeutic compounds.

This Special Issue of Cancers will publish a collection of short reports, original research, and clinical articles, as well as reviews at the area of the Genomic Landscape of Breast Cancers: from Primary to Metastasis. Of special interest are studies describing metastasis-acquired alterations with a focus on functionally relevant alterations that may be organ-specific or commonly shared. The main scope is to highlight current developments in the genomic profiling of breast cancers, including the identification of novel genomic targets and/or biomarkers of clinical response.

Dr. Athina Giannoudis
Dr. Damir Vareslija
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. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • breast cancer
  • metastasis
  • genomic profile
  • mutations
  • copy number variations
  • targeted therapies
  • biomarkers

Published Papers (7 papers)

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Research

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17 pages, 8250 KiB  
Article
Integrated Proteogenomic Analysis Reveals Distinct Potentially Actionable Therapeutic Vulnerabilities in Triple-Negative Breast Cancer Subtypes
by Pushpinder Kaur, Alexander Ring, Tania B. Porras, Guang Zhou, Janice Lu, Irene Kang and Julie E. Lang
Cancers 2024, 16(3), 516; https://doi.org/10.3390/cancers16030516 - 25 Jan 2024
Viewed by 940
Abstract
Triple-negative breast cancer (TNBC) is characterized by an aggressive clinical presentation and a paucity of clinically actionable genomic alterations. Here, we utilized the Cancer Genome Atlas (TCGA) to explore the proteogenomic landscape of TNBC subtypes to see whether genomic alterations can be inferred [...] Read more.
Triple-negative breast cancer (TNBC) is characterized by an aggressive clinical presentation and a paucity of clinically actionable genomic alterations. Here, we utilized the Cancer Genome Atlas (TCGA) to explore the proteogenomic landscape of TNBC subtypes to see whether genomic alterations can be inferred from proteomic data. We found only 4% of the protein level changes are explained by mutations, while 21% of the protein and 35% of the transcriptomics changes were determined by copy number alterations (CNAs). We found tighter coupling between proteome and genome in some genes that are predicted to be the targets of drug inhibitors, including CDKs, PI3K, tyrosine kinase (TKI), and mTOR. The validation of our proteogenomic workflow using mass spectrometry Clinical Proteomic Tumor Analysis Consortium (MS-CPTAC) data also demonstrated the highest correlation between protein–RNA–CNA. The integrated proteogenomic approach helps to prioritize potentially actionable targets and may enable the acceleration of personalized cancer treatment. Full article
(This article belongs to the Special Issue Genomic Landscape of Breast Cancer: From Primary to Metastasis)
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17 pages, 4671 KiB  
Article
Differences in the Molecular Profile between Primary Breast Carcinomas and Their Cutaneous Metastases
by Silvia González-Martínez, David Pizarro, Belén Pérez-Mies, Tamara Caniego-Casas, José Luis Rodríguez-Peralto, Giuseppe Curigliano, Alfonso Cortés, María Gión, Javier Cortés and José Palacios
Cancers 2022, 14(5), 1151; https://doi.org/10.3390/cancers14051151 - 23 Feb 2022
Cited by 5 | Viewed by 1970
Abstract
Background: The characterization of molecular alterations of primary breast carcinomas (BC) and their cutaneous metastases (CM) to identify genes involved in the metastatic process have not yet been completely accomplished. Methods: To investigate the molecular alterations of BC and their CM, a total [...] Read more.
Background: The characterization of molecular alterations of primary breast carcinomas (BC) and their cutaneous metastases (CM) to identify genes involved in the metastatic process have not yet been completely accomplished. Methods: To investigate the molecular alterations of BC and their CM, a total of 66 samples (33 BC and 33 CM) from 33 patients were analyzed by immunohistochemical and massive parallel sequencing analyses. In addition, the clinicopathological characteristics of patients and tumors were analyzed. Results: Triple negative (TN) BCs were overrepresented (36.4%) among tumors that developed CM. A change of tumor surrogate molecular type in metastases was found in 15% of patients and 48.5% of the CM presented some additional molecular alteration with respect to the primary tumor, the most frequent were amplification of MYC and MDM4, and mutations in TP53 and PIK3CA. Survival was related to histological grade, tumor surrogate molecular type and TP53 mutations in the univariate analysis but only the tumor surrogate molecular type remained as a prognostic factor in the multivariate analysis. Conclusions: The TN molecular type has a greater risk of developing skin metastases. There are phenotypic changes and additional molecular alterations in skin metastases compared to the corresponding primary breast tumors in nearly half of the patients. Although these changes do not follow a specific pattern and varied from patient to patient, they could impact on the treatment. More studies with larger patient and sample cohorts are needed. Full article
(This article belongs to the Special Issue Genomic Landscape of Breast Cancer: From Primary to Metastasis)
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12 pages, 3123 KiB  
Article
An Integrated Epigenomic and Genomic View on Phyllodes and Phyllodes-like Breast Tumors
by Juergen Hench, Tatjana Vlajnic, Savas Deniz Soysal, Ellen C. Obermann, Stephan Frank and Simone Muenst
Cancers 2022, 14(3), 667; https://doi.org/10.3390/cancers14030667 - 28 Jan 2022
Cited by 7 | Viewed by 2780
Abstract
Fibroepithelial lesions (FL) of the breast, in particular, phyllodes tumors (PT) and fibroadenomas, pose a significant diagnostic challenge. There are no generally accepted criteria that distinguish benign, borderline, malignant PT and fibroadenomas. Combined genome-wide DNA methylation and copy number variant (CNV) profiling is [...] Read more.
Fibroepithelial lesions (FL) of the breast, in particular, phyllodes tumors (PT) and fibroadenomas, pose a significant diagnostic challenge. There are no generally accepted criteria that distinguish benign, borderline, malignant PT and fibroadenomas. Combined genome-wide DNA methylation and copy number variant (CNV) profiling is an emerging strategy to classify tumors. We compiled a series of patient-derived archival biopsy specimens reflecting the FL spectrum and histological mimickers including clinical follow-up data. DNA methylation and CNVs were determined by well-established microarrays. Comparison of the patterns with a pan-cancer dataset assembled from public resources including “The Cancer Genome Atlas” (TCGA) and “Gene Expression Omnibus” (GEO) suggests that FLs form a methylation class distinct from both control breast tissue as well as common breast cancers. Complex CNVs were enriched in clinically aggressive FLs. Subsequent fluorescence in situ hybridization (FISH) analysis detected respective aberrations in the neoplastic mesenchymal component of FLs only, confirming that the epithelial component is non-neoplastic. Of note, our approach could lead to the elimination of the diagnostically problematic category of borderline PT and allow for optimized prognostic patient stratification. Furthermore, the identified recurrent genomic aberrations such as 1q gains (including MDM4), CDKN2a/b deletions, and EGFR amplifications may inform therapeutic decision-making. Full article
(This article belongs to the Special Issue Genomic Landscape of Breast Cancer: From Primary to Metastasis)
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15 pages, 2986 KiB  
Article
Ribociclib Induces Broad Chemotherapy Resistance and EGFR Dependency in ESR1 Wildtype and Mutant Breast Cancer
by Isabel Mayayo-Peralta, Beatrice Faggion, Liesbeth Hoekman, Ben Morris, Cor Lieftink, Isabella Goldsbrough, Lakjaya Buluwela, Joseph C. Siefert, Harm Post, Maarten Altelaar, Roderick Beijersbergen, Simak Ali, Wilbert Zwart and Stefan Prekovic
Cancers 2021, 13(24), 6314; https://doi.org/10.3390/cancers13246314 - 16 Dec 2021
Cited by 4 | Viewed by 4533
Abstract
While endocrine therapy is highly effective for the treatment of oestrogen receptor-α (ERα)-positive breast cancer, a significant number of patients will eventually experience disease progression and develop treatment-resistant, metastatic cancer. The majority of resistant tumours remain dependent on ERα-action, with activating ESR1 gene [...] Read more.
While endocrine therapy is highly effective for the treatment of oestrogen receptor-α (ERα)-positive breast cancer, a significant number of patients will eventually experience disease progression and develop treatment-resistant, metastatic cancer. The majority of resistant tumours remain dependent on ERα-action, with activating ESR1 gene mutations occurring in 15–40% of advanced cancers. Therefore, there is an urgent need to discover novel effective therapies that can eradicate cancer cells with aberrant ERα and to understand the cellular response underlying their action. Here, we evaluate the response of MCF7-derived, CRISPR-Cas9-generated cell lines expressing mutant ERα (Y537S) to a large number of drugs. We report sensitivity to numerous clinically approved inhibitors, including CDK4/6 inhibitor ribociclib, which is a standard-of-care therapy in the treatment of metastatic ERα-positive breast cancer and currently under evaluation in the neoadjuvant setting. Ribociclib treatment induces senescence in both wildtype and mutant ERα breast cancer models and leads to a broad-range drug tolerance. Strikingly, viability of cells undergoing ribociclib-induced cellular senescence is maintained via engagement of EGFR signalling, which may be therapeutically exploited in both wildtype and mutant ERα-positive breast cancer. Our study highlights a wide-spread reduction in sensitivity to anti-cancer drugs accompanied with an acquired vulnerability to EGFR inhibitors following CDK4/6 inhibitor treatment. Full article
(This article belongs to the Special Issue Genomic Landscape of Breast Cancer: From Primary to Metastasis)
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Review

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31 pages, 2378 KiB  
Review
Targeting the Heterogeneous Genomic Landscape in Triple-Negative Breast Cancer through Inhibitors of the Transcriptional Machinery
by Vera E. van der Noord, Bob van de Water and Sylvia E. Le Dévédec
Cancers 2022, 14(18), 4353; https://doi.org/10.3390/cancers14184353 - 07 Sep 2022
Cited by 4 | Viewed by 3425
Abstract
Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer defined by lack of the estrogen, progesterone and human epidermal growth factor receptor 2. Although TNBC tumors contain a wide variety of oncogenic mutations and copy number alterations, the direct targeting of [...] Read more.
Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer defined by lack of the estrogen, progesterone and human epidermal growth factor receptor 2. Although TNBC tumors contain a wide variety of oncogenic mutations and copy number alterations, the direct targeting of these alterations has failed to substantially improve therapeutic efficacy. This efficacy is strongly limited by interpatient and intratumor heterogeneity, and thereby a lack in uniformity of targetable drivers. Most of these genetic abnormalities eventually drive specific transcriptional programs, which may be a general underlying vulnerability. Currently, there are multiple selective inhibitors, which target the transcriptional machinery through transcriptional cyclin-dependent kinases (CDKs) 7, 8, 9, 12 and 13 and bromodomain extra-terminal motif (BET) proteins, including BRD4. In this review, we discuss how inhibitors of the transcriptional machinery can effectively target genetic abnormalities in TNBC, and how these abnormalities can influence sensitivity to these inhibitors. These inhibitors target the genomic landscape in TNBC by specifically suppressing MYC-driven transcription, inducing further DNA damage, improving anti-cancer immunity, and preventing drug resistance against MAPK and PI3K-targeted therapies. Because the transcriptional machinery enables transcription and propagation of multiple cancer drivers, it may be a promising target for (combination) treatment, especially of heterogeneous malignancies, including TNBC. Full article
(This article belongs to the Special Issue Genomic Landscape of Breast Cancer: From Primary to Metastasis)
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18 pages, 767 KiB  
Review
PARP Inhibitors for Breast Cancer: Germline BRCA1/2 and Beyond
by Maria Clara Saad Menezes, Farah Raheem, Lida Mina, Brenda Ernst and Felipe Batalini
Cancers 2022, 14(17), 4332; https://doi.org/10.3390/cancers14174332 - 05 Sep 2022
Cited by 16 | Viewed by 3483
Abstract
Poly-adenosine diphosphate ribose polymerase (PARP) inhibitors (PARPi) are approved for BRCA1/2 carriers with HER2-negative breast cancer in the adjuvant setting with a high risk of recurrence as well as the metastatic setting. However, the indications for PARPi are broader for patients with other [...] Read more.
Poly-adenosine diphosphate ribose polymerase (PARP) inhibitors (PARPi) are approved for BRCA1/2 carriers with HER2-negative breast cancer in the adjuvant setting with a high risk of recurrence as well as the metastatic setting. However, the indications for PARPi are broader for patients with other cancer types (e.g., prostate and ovarian cancer), involving additional biomarkers (e.g., ATM, PALB2, and CHEK) and genomic instability scores. Herein, we summarize the data on PARPi and breast cancer and discuss their use beyond BRCA carriers. Full article
(This article belongs to the Special Issue Genomic Landscape of Breast Cancer: From Primary to Metastasis)
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18 pages, 1798 KiB  
Review
Breast Cancer Genomics: Primary and Most Common Metastases
by Caroline Bennett, Caleb Carroll, Cooper Wright, Barbara Awad, Jeong Mi Park, Meagan Farmer, Elizabeth (Bryce) Brown, Alexis Heatherly and Stefanie Woodard
Cancers 2022, 14(13), 3046; https://doi.org/10.3390/cancers14133046 - 21 Jun 2022
Cited by 4 | Viewed by 2921
Abstract
Specific genomic alterations have been found in primary breast cancer involving driver mutations that result in tumorigenesis. Metastatic breast cancer, which is uncommon at the time of disease onset, variably impacts patients throughout the course of their disease. Both the molecular profiles and [...] Read more.
Specific genomic alterations have been found in primary breast cancer involving driver mutations that result in tumorigenesis. Metastatic breast cancer, which is uncommon at the time of disease onset, variably impacts patients throughout the course of their disease. Both the molecular profiles and diverse genomic pathways vary in the development and progression of metastatic breast cancer. From the most common metastatic site (bone), to the rare sites such as orbital, gynecologic, or pancreatic metastases, different levels of gene expression indicate the potential involvement of numerous genes in the development and spread of breast cancer. Knowledge of these alterations can, not only help predict future disease, but also lead to advancement in breast cancer treatments. This review discusses the somatic landscape of breast primary and metastatic tumors. Full article
(This article belongs to the Special Issue Genomic Landscape of Breast Cancer: From Primary to Metastasis)
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