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Cancers
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Breast Cancer Metastasis: Novel Insights into Molecular Mechanisms and Treatments
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Breast Cancer Metastasis: Novel Insights into Molecular Mechanisms and Treatments

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

Deadline for manuscript submissions: 5 June 2025 | Viewed by 14763

Special Issue Editor

Dr. Delphine Denoyer

E-Mail
Guest Editor
Matrix Microenvironment & Metastasis Laboratory, Translational Breast Cancer Program, Olivia Newton-John Cancer Research Institute, Melbourne, Australia
Interests: breast cancer; metastasis; ferroptosis; tyrosine kinase inhibitors; extracellular matrix; integrins; molecular imaging (PET and SPECT, high resolution autoradiography); radionuclide therapy; metallomics

Special Issue Information

Dear Colleagues,

Breast cancer has become the most diagnosed cancer worldwide with about 685,000 deaths recorded in 2020. Metastases are responsible for approximately 90% of breast cancer-related deaths and, despite treatment advances, they remain largely incurable. Breast cancer preferentially metastasizes to bones, lungs, liver, and brain. However, molecular features dictating site-specific metastasis and differential responses to therapy are still poorly understood. Therefore, a better comprehension of how metastatic breast cancer cells interact with their microenvironment is essential for the design of tailored treatments.

We are pleased to invite you to contribute to this Special Issue entitled “Breast Cancer Metastasis: Novel Insights into Molecular Mechanisms and Treatments” that aims to provide the latest key findings in the field of basic and translational research on metastatic breast cancer. In this Special Issue, original research articles and reviews are welcome. Research areas may include (but are not limited to) the following: cellular and molecular mechanisms regulating organ-specific metastasis and tumor dormancy, biomarker discovery, and advancements in therapeutic approaches for the various breast cancer subtypes, including small-molecule inhibitors and immunotherapy.

We look forward to receiving your contributions.

Dr. Delphine Denoyer
Guest Editor

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 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
  • organ-specific metastasis
  • cellular and molecular mechanisms
  • biomarkers
  • response to treatments
  • small-molecule inhibitors
  • immunotherapy
  • tumor dormancy

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Published Papers (7 papers)

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Research

23 pages, 5720 KiB  
Article
ANKRD1 Promotes Breast Cancer Metastasis by Activating NF-κB-MAGE-A6 Pathway
by Penchatr Diskul-Na-Ayudthaya, Seon Joo Bae, Yun-Ui Bae, Ngu Trinh Van, Wootae Kim and Seongho Ryu
Cancers 2024, 16(19), 3306; https://doi.org/10.3390/cancers16193306 - 27 Sep 2024
Cited by 1 | Viewed by 1539
Abstract
Early detection and surgical excision of tumors have helped improve the survival rate of patients with breast cancer. However, patients with metastatic cancer typically have a poor prognosis. In this study, we propose that ANKRD1 promotes metastasis of breast cancer. ANKRD1 was found [...] Read more.
Early detection and surgical excision of tumors have helped improve the survival rate of patients with breast cancer. However, patients with metastatic cancer typically have a poor prognosis. In this study, we propose that ANKRD1 promotes metastasis of breast cancer. ANKRD1 was found to be highly expressed in the MDA-MB-231 and MDA-LM-2 highly metastatic breast cancer cell lines compared to the non-metastatic breast cancer cell lines (MCF-7, ZR-75-30, T47D) and normal breast cancer cells (MCF-10A). Furthermore, high-grade tumors showed increased levels of ANKRD1 compared to low-grade tumors. Both in vitro and in vivo functional studies demonstrated the essential role of ANKRD1 in cancer cell migration and invasion. The previous studies have suggested a significant role of NF-κB and MAGE-A6 in breast cancer metastasis, but the upstream regulators of this axis are not well characterized. Our study suggests that ANKRD1 promotes metastasis of breast cancer by activating NF-κB as well as MAGE-A6 signaling. Our findings show that ANKRD1 is a potential therapeutic target and a diagnostic marker for breast cancer metastasis. Full article
(This article belongs to the Special Issue Breast Cancer Metastasis: Novel Insights into Molecular Mechanisms and Treatments)
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28 pages, 3204 KiB  
Article
The RAL Small G Proteins Are Clinically Relevant Targets in Triple Negative Breast Cancer
by David Han, Jonathan M. Spehar, Dillon S. Richardson, Sumudu Leelananda, Prathik Chakravarthy, Samantha Grecco, Jesse Reardon, Daniel G. Stover, Chad Bennett, Gina M. Sizemore, Zaibo Li, Steffen Lindert and Steven T. Sizemore
Cancers 2024, 16(17), 3043; https://doi.org/10.3390/cancers16173043 - 31 Aug 2024
Viewed by 1783
Abstract
Breast cancer (BC) is the most frequent cancer and second-leading cause of cancer deaths in women in the United States. While RAS mutations are infrequent in BC, triple-negative (TN) and HER2-positive (HER2+) BC both exhibit increased RAS activity. Here, we tested the RAS [...] Read more.
Breast cancer (BC) is the most frequent cancer and second-leading cause of cancer deaths in women in the United States. While RAS mutations are infrequent in BC, triple-negative (TN) and HER2-positive (HER2+) BC both exhibit increased RAS activity. Here, we tested the RAS effectors RALA and RALB, which are overexpressed in BC, as tractable molecular targets in these subtypes. While analysis of the breast cancer patient sample data suggests that the RALs are associated with poor outcome in both TNBC and HER2+ BC, our in vivo and in vitro experimental findings revealed the RALs to be essential in only the TNBC cell lines. While testing the response of the BC cell lines to the RAL inhibitors RBC8 and BQU57, we observed no correlation between drug efficacy and cell line dependency on RAL expression for survival, suggesting that these compounds kill via off-target effects. Finally, we report the discovery of a new small molecule inhibitor, OSURALi, which exhibits strong RAL binding, effectively inhibits RAL activation, and is significantly more toxic to RAL-dependent TNBC cells than RAL-independent HER2+ and normal cell lines. These results support the RALs as viable molecular targets in TNBC and the further investigation of OSURALi as a therapeutic agent. Full article
(This article belongs to the Special Issue Breast Cancer Metastasis: Novel Insights into Molecular Mechanisms and Treatments)
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14 pages, 1125 KiB  
Article
Estrogen-Receptor Loss and ESR1 Mutation in Estrogen-Receptor-Positive Metastatic Breast Cancer and the Effect on Overall Survival
by Pieter J. Westenend, Claudia J. C. Meurs, Bertie de Leeuw and Robert C. Akkers
Cancers 2024, 16(17), 3025; https://doi.org/10.3390/cancers16173025 - 30 Aug 2024
Viewed by 1544
Abstract
In patients with metastatic estrogen-receptor (ER)-positive HER2-negative breast cancer, the loss of ER expression and the mutation of ESR1—the gene encoding the ER receptor—are mechanisms for resistance to endocrine therapy. We aimed to determine the frequency of these mechanisms and their interaction. [...] Read more.
In patients with metastatic estrogen-receptor (ER)-positive HER2-negative breast cancer, the loss of ER expression and the mutation of ESR1—the gene encoding the ER receptor—are mechanisms for resistance to endocrine therapy. We aimed to determine the frequency of these mechanisms and their interaction. Metastases were retrieved from our pathology files. ESR1 hotspot mutations resulting in p.(D538G), p.(Y537S), and p.(L536H) were determined by means of pyrosequencing. Clinical data were retrieved from electronic medical records. A total of 136 metastases were available for analysis. ER loss was found in 23 metastases (17%). ESR1 mutations were found in 18 metastases (13%), including p.(D538G) in 9, p.(Y537S) in 7, and p.(L536H) in 2. ESR1 mutation and ER loss were mutually exclusive (p = 0.042), and ESR1 mutation was associated with endocrine therapy (p = 0.002). ESR1 mutation was found in two primary breast cancers. ESR1 mutations are rare in primary breast cancer and develop in metastases during endocrine therapy. Furthermore, ER loss had a statistically significant negative effect on overall survival when compared to patients without ER loss, with a rate ratio of 3.21 (confidence interval 1.95–5.26). No such effect was observed for ESR1 mutations, with a rate ratio of 1.15 (confidence interval 0.67–1.95). We conclude that ER loss and ESR1 mutation together account for 30% of the resistance to endocrine therapy. Full article
(This article belongs to the Special Issue Breast Cancer Metastasis: Novel Insights into Molecular Mechanisms and Treatments)
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14 pages, 4218 KiB  
Article
Differential Serum Peptidomics Reveal Multi-Marker Models That Predict Breast Cancer Progression
by Adhari AlZaabi, Stephen Piccolo, Steven Graves and Marc Hansen
Cancers 2024, 16(13), 2365; https://doi.org/10.3390/cancers16132365 - 27 Jun 2024
Viewed by 1133
Abstract
Here, we assess how the differential expression of low molecular weight serum peptides might predict breast cancer progression with high confidence. We apply an LC/MS-MS-based, unbiased ‘omics’ analysis of serum samples from breast cancer patients to identify molecules that are differentially expressed in [...] Read more.
Here, we assess how the differential expression of low molecular weight serum peptides might predict breast cancer progression with high confidence. We apply an LC/MS-MS-based, unbiased ‘omics’ analysis of serum samples from breast cancer patients to identify molecules that are differentially expressed in stage I and III breast cancer. Results were generated using standard and machine learning-based analytical workflows. With standard workflow, a discovery study yielded 65 circulating biomarker candidates with statistically significant differential expression. A second study confirmed the differential expression of a subset of these markers. Models based on combinations of multiple biomarkers were generated using an exploratory algorithm designed to generate greater diagnostic power and accuracy than any individual markers. Individual biomarkers and the more complex multi-marker models were then tested in a blinded validation study. The multi-marker models retained their predictive power in the validation study, the best of which attained an AUC of 0.84, with a sensitivity of 43% and a specificity of 88%. One of the markers with m/z 761.38, which was downregulated, was identified as a fibrinogen alpha chain. Machine learning-based analysis yielded a classifier that correctly categorizes every subject in the study and demonstrates parameter constraints required for high confidence in classifier output. These results suggest that serum peptide biomarker models could be optimized to assess breast cancer stage in a clinical setting. Full article
(This article belongs to the Special Issue Breast Cancer Metastasis: Novel Insights into Molecular Mechanisms and Treatments)
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15 pages, 1661 KiB  
Article
Breast Cancer and Bone Mineral Density in a U.S. Cohort of Middle-Aged Women: Associations with Phosphate Toxicity
by Ronald B. Brown, Philip Bigelow and Joel A. Dubin
Cancers 2023, 15(20), 5093; https://doi.org/10.3390/cancers15205093 - 21 Oct 2023
Cited by 4 | Viewed by 2829
Abstract
Breast cancer is associated with phosphate toxicity, the toxic effect from dysregulated phosphate metabolism that can stimulate tumorigenesis. Phosphate toxicity and dysregulated phosphate metabolism are also associated with bone mineral abnormalities, including excessive bone mineral loss and deposition. Based on shared associations with [...] Read more.
Breast cancer is associated with phosphate toxicity, the toxic effect from dysregulated phosphate metabolism that can stimulate tumorigenesis. Phosphate toxicity and dysregulated phosphate metabolism are also associated with bone mineral abnormalities, including excessive bone mineral loss and deposition. Based on shared associations with dysregulated phosphate metabolism and phosphate toxicity, a hypothesis proposed in the present mixed methods–grounded theory study posits that middle-aged women with incidence of breast cancer had a greater magnitude of changes in bone mineral density over time compared with women who remained cancer-free. To test this hypothesis, a mixed-effects model was used to analyze the associations of breast cancer incidence with spinal bone mineral density changes in the U.S. Study of Women’s Health Across the Nation. Compared with women in the cohort who remained cancer-free, women who self-reported breast cancer had higher bone mineral density at baseline, but had more rapid losses in bone mineral density during follow-up visits. These findings agree with the hypothesis that a greater magnitude of changes in bone mineral density over time is associated with breast cancer in a cohort of middle-aged women. The findings also have implications for studies investigating dysregulated phosphate metabolism and phosphate toxicity as causative factors of bone metastasis in metastatic breast cancer. Additionally, the authors previously found increased breast cancer risk associated with high dietary phosphate intake in the same cohort of middle-aged women, and more studies should investigate a low-phosphorus diet to reduce bone mineral abnormalities and tumorigenesis in breast cancer patients. Full article
(This article belongs to the Special Issue Breast Cancer Metastasis: Novel Insights into Molecular Mechanisms and Treatments)
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23 pages, 3825 KiB  
Article
PTHrP Regulates Fatty Acid Metabolism via Novel lncRNA in Breast Cancer Initiation and Progression Models
by Rui Zhang, Jiarong Li, Dunarel Badescu, Andrew C. Karaplis, Jiannis Ragoussis and Richard Kremer
Cancers 2023, 15(15), 3763; https://doi.org/10.3390/cancers15153763 - 25 Jul 2023
Cited by 2 | Viewed by 2100
Abstract
Parathyroid hormone-related peptide (PTHrP) is the primary cause of malignancy-associated hypercalcemia (MAH). We previously showed that PTHrP ablation, in the MMTV-PyMT murine model of breast cancer (BC) progression, can dramatically prolong tumor latency, slow tumor growth, and prevent metastatic spread. However, the signaling [...] Read more.
Parathyroid hormone-related peptide (PTHrP) is the primary cause of malignancy-associated hypercalcemia (MAH). We previously showed that PTHrP ablation, in the MMTV-PyMT murine model of breast cancer (BC) progression, can dramatically prolong tumor latency, slow tumor growth, and prevent metastatic spread. However, the signaling mechanisms using lineage tracing have not yet been carefully analyzed. Here, we generated Pthrpflox/flox; Cre+ mT/mG mice (KO) and Pthrpwt/wt; Cre+ mT/mG tumor mice (WT) to examine the signaling pathways under the control of PTHrP from the early to late stages of tumorigenesis. GFP+ mammary epithelial cells were further enriched for subsequent RNA sequencing (RNAseq) analyses. We observed significant upregulation of cell cycle signaling and fatty acid metabolism in PTHrP WT tumors, which are linked to tumor initiation and progression. Next, we observed that the expression levels of a novel lncRNA, GM50337, along with stearoyl-Coenzyme A desaturase 1 (Scd1) are significantly upregulated in PTHrP WT but not in KO tumors. We further validated a potential human orthologue lncRNA, OLMALINC, together with SCD1 that can be regulated via PTHrP in human BC cell lines. In conclusion, these novel findings could be used to develop targeted strategies for the treatment of BC and its metastatic complications. Full article
(This article belongs to the Special Issue Breast Cancer Metastasis: Novel Insights into Molecular Mechanisms and Treatments)
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12 pages, 2916 KiB  
Article
Loco-Regional Treatment of the Primary Tumor in De Novo Metastatic Breast Cancer Patients Undergoing Front-Line Chemotherapy
by Corrado Tinterri, Andrea Sagona, Erika Barbieri, Simone Di Maria Grimaldi, Flavia Jacobs, Alberto Zambelli, Rubina Manuela Trimboli, Daniela Bernardi, Valeriano Vinci and Damiano Gentile
Cancers 2022, 14(24), 6237; https://doi.org/10.3390/cancers14246237 - 17 Dec 2022
Cited by 13 | Viewed by 2309
Abstract
Background: Loco-regional therapy (LRT) in de novo metastatic breast cancer (MBC) has been investigated in several clinical trials, with heterogeneous and conflicting results. Methods: We conducted a retrospective study of de novo MBC patients treated with front-line chemotherapy (FLC) followed by LRT of [...] Read more.
Background: Loco-regional therapy (LRT) in de novo metastatic breast cancer (MBC) has been investigated in several clinical trials, with heterogeneous and conflicting results. Methods: We conducted a retrospective study of de novo MBC patients treated with front-line chemotherapy (FLC) followed by LRT of the primary tumor. Our aims were to evaluate the characteristics, treatment, and oncological outcomes in terms of progression-free survival (PFS), distant progression-free survival (DPFS), and overall survival (OS) of de novo MBC. We also investigated possible subgroups of patients with better outcomes according to menopausal status, biological sub-type, location, number of metastases, and radiologic complete response after FLC. Results: We included 61 patients in the study. After a median follow-up of 55 months, disease progression occurred in 60.7% of patients and 49.2% died. There were no significant differences in PFS, DPFS, and OS between different subgroups of de novo MBC patients. A trend toward better PFS and DPFS was observed in triple-positive tumors, without a statistically significant difference in OS. Conclusions: No specific subgroup of de novo MBC patients showed a statistically significant survival advantage after FLC followed by LRT of the primary tumor. Full article
(This article belongs to the Special Issue Breast Cancer Metastasis: Novel Insights into Molecular Mechanisms and Treatments)
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