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Breast Cancer, Metastatic Breast Cancer, Therapeutic Approaches, 2nd Edition

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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: closed (31 October 2024) | Viewed by 14607

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Dr. Mi Kyung Park

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1. Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy National Cance Center, Goyang 10408, Republic of Korea
2. Department of Bio-Healthcare, Hwasung Medi-Science University, Hwaseong-si 18274, Republic of Korea
Interests: molecular mechanism; tumor microenvironment; epithelial-to-mesenchymal transition (EMT); post-translational modification (PTM); autophagy; potential therapeutic approaches; preclinical mouse models for cancers; breast cancer; liver cancer; lung cancer; pancreatic cancer; cancer progression and metastasis
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Dear Colleagues,

Breast cancers are heterogeneous and have a multistep progression at molecular and morphologic levels during tumor development. Metastatic breast cancer is a cancer that originated from the breast and that has dispersed into the lymph nodes or to several other sites, such as the bone, liver, lung, or brain, and has acquired genetic and epigenetic alterations in cancer cells. The molecular mechanisms of the epithelial-to-mesenchymal transition (EMT) are provided as therapeutic targets in metastatic breast cancer. Metastasis is a multistage process that is involved in various epigenetic and post-translational modifications (PTMs) during breast cancer progression and metastasis. The remodeling between the tumor microenvironment and the extracellular matrix (ECM) is also essential for metastasis. Various elements of the breast tumor microenvironment enhance metastatic progression.

This Special Issue, “Breast Cancer, Metastatic Breast Cancer, Therapeutic Approaches 2.0”, aims to provide a platform for obtaining new deeper insights into the molecular mechanisms and potential therapeutic approaches in cancer. Authors are invited to submit original research and topical review articles on these topics.

Dr. Mi Kyung Park
Guest Editor

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Keywords

breast cancer
metastatic breast cancer
epithelial-to-mesenchymal transition (EMT)
epigenetic and post-translational modifications (PTM)
tumor microenvironment

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Related Special Issue

Molecular Mechanism and Therapeutic Approaches of Breast Cancer, Metastatic Breast Cancer, 3rd Edition in International Journal of Molecular Sciences

Published Papers (9 papers)

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Research

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12 pages, 903 KiB

Open AccessArticle

Association of Granulocyte Colony-Stimulating Factor Treatment with Risk of Brain Metastasis in Advanced Stage Breast Cancer

by Yun-Sheng Tai, John Hang Leung, Shyh-Yau Wang, Henry W. C. Leung and Agnes L. F. Chan

Int. J. Mol. Sci. 2024, 25(19), 10756; https://doi.org/10.3390/ijms251910756 - 6 Oct 2024

Viewed by 794

Abstract

The routine use of granulocyte colony-stimulating factor (GCSF) is not recommended for the prevention or treatment of chemotherapy-induced neutropenia or febrile neutropenia because risks associated with certain types of cancers, distant organ metastases, and primary tumor growth cannot be excluded. We examined the association between GCSF use and the incidence of brain metastasis (BM), as well as BM-free survival (BMFS). This retrospective cohort study included 121 stage IV breast cancer patients without confirmed BM at the time of diagnosis and who received at least one course of systematic chemotherapy or target therapy at a tertiary teaching hospital between 1 January 2014 and 31 December 2022. The effect of GCSF use on BM was assessed with other confounding factors in Cox regression analyses. In this retrospective cohort, patients who received GCSF treatment had a significantly higher incidence of BM than those who did not (34.9% vs. 13.8%, p = 0.011). Univariate Cox regression analysis showed that GCSF use, menopause status, hormone treatment, HER2 treatment, cumulative dosage, dosage density, and neutropenia were independent risk factors for BMFS (p < 0.05). GCSF users had a higher risk of BM (adjusted HR: 2.538; 95% CI: 1.127–5.716, p = 0.025) than nonusers. BM risk was significantly associated with those with neutropenia (RR: 1.84, 95% CI: 1.21, 2.80) but not with those without neutropenia (RR: 0.59, 95% CI: 0.41–0.84, Interaction p-value < 0.05). The higher the dose density of GCSF, the higher the risk compared with those who do not use GCSF (p for trend < 0.01). These preliminary results suggest that GCSF is associated with BM in patients with stage IV breast cancer who did not have BM at initial diagnosis. Further comprehensively designed large-scale observational studies are needed to confirm our preliminary results. Full article

(This article belongs to the Special Issue Breast Cancer, Metastatic Breast Cancer, Therapeutic Approaches, 2nd Edition)

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12 pages, 5014 KiB

Open AccessArticle

Insights into E-Cadherin Impairment in CDH1-Unaltered Invasive Lobular Carcinoma: A Comprehensive Bioinformatic Study

by Shiro Uchida and Takashi Sugino

Int. J. Mol. Sci. 2024, 25(16), 8961; https://doi.org/10.3390/ijms25168961 - 17 Aug 2024

Viewed by 802

Abstract

Invasive lobular carcinoma exhibits unique morphological features frequently associated with alterations in CDH1. Although some studies have identified abnormalities in adhesion factors other than E-cadherin, the molecular mechanisms underlying E-cadherin abnormalities in CDH1-unaltered invasive lobular carcinoma remain poorly understood. In this study, we investigated the molecular underpinnings of E-cadherin dysregulation in invasive lobular carcinoma in the absence of CDH1 gene alterations, using comprehensive bioinformatic analyses. We conducted a comparative study of CDH1-mutated and non-mutated invasive lobular carcinoma and evaluated the differences in mRNA levels, reverse-phase protein array, methylation, and miRNAs. We observed that invasive lobular carcinoma cases without CDH1 alterations exhibited a significantly higher incidence of the Claudin-low subtype (p < 0.01). The results of the reverse-phase protein array indicate no significant difference in E-cadherin expression between CDH1-mutated and non-mutated cases. Therefore, abnormalities in E-cadherin production also exist in CDH1 non-mutated invasive lobular carcinoma. Considering that there are no differences in mRNA levels and methylation status, post-translational modifications are the most plausible explanation for the same. Hence, future studies should focus on elucidating the mechanism underlying E-cadherin inactivation via post-translational modifications in CDH1 non-mutated invasive lobular carcinoma. Full article

(This article belongs to the Special Issue Breast Cancer, Metastatic Breast Cancer, Therapeutic Approaches, 2nd Edition)

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13 pages, 4385 KiB

Open AccessArticle

β-D-Glucose-Reduced Silver Nanoparticles Remodel the Tumor Microenvironment in a Murine Model of Triple-Negative Breast Cancer

by Pedro Félix-Piña, Moisés Armides Franco Molina, Paola Leonor García Coronado, Heriberto Prado-Garcia, Diana Ginette Zarate-Triviño, Beatriz Elena Castro-Valenzuela, Kenia Arisbe Moreno-Amador, Ashanti Concepción Uscanga Palomeque and Cristina Rodríguez Padilla

Int. J. Mol. Sci. 2024, 25(15), 8432; https://doi.org/10.3390/ijms25158432 - 2 Aug 2024

Viewed by 908

Abstract

Breast cancer is the most diagnosed type of cancer worldwide and the second cause of death in women. Triple-negative breast cancer (TNBC) is the most aggressive, and due to the lack of specific targets, it is considered the most challenging subtype to treat and the subtype with the worst prognosis. The present study aims to determine the antitumor effect of beta-D-glucose-reduced silver nanoparticles (AgNPs-G) in a murine model of TNBC, as well as to study its effect on the tumor microenvironment. In an airbag model with 4T1 tumor cell implantation, the administration of AgNPs-G or doxorubicin showed antitumoral activity. Using immunohistochemistry it was demonstrated that treatment with AgNPs-G decreased the expression of PCNA, IDO, and GAL-3 and increased the expression of Caspase-3. In the tumor microenvironment, the treatment increased the percentage of memory T cells and innate effector cells and decreased CD4+ cells and regulatory T cells. There was also an increase in the levels of TNF-α, IFN-γ, and IL-6, while TNF-α was increased in serum. In conclusion, we suggest that AgNPs-G treatment has an antitumor effect that is demonstrated by its ability to remodel the tumor microenvironment in mice with TNBC. Full article

(This article belongs to the Special Issue Breast Cancer, Metastatic Breast Cancer, Therapeutic Approaches, 2nd Edition)

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17 pages, 7300 KiB

Open AccessArticle

Ibulocydine Inhibits Migration and Invasion of TNBC Cells via MMP-9 Regulation

by Mi-Ri Kwon, Ji-Soo Park, Eun-Jung Ko, Jin Park, Eun-Jin Ju, Seol-Hwa Shin, Ga-Won Son, Hye-Won Lee, Yun-Yong Park, Myoung-Hee Kang, Yeon-Joo Kim, Byeong-Moon Kim, Hee-Jin Lee, Tae-Won Kim, Chong-Jai Kim, Si-Yeol Song, Seok-Soon Park and Seong-Yun Jeong

Int. J. Mol. Sci. 2024, 25(11), 6123; https://doi.org/10.3390/ijms25116123 - 1 Jun 2024

Viewed by 988

Abstract

Triple-negative breast cancer (TNBC) accounts for approximately 15–20% of all breast cancer types, indicating a poor survival prognosis with a more aggressive biology of metastasis to the lung and a short response duration to available therapies. Ibulocydine (IB) is a novel (cyclin-dependent kinase) CDK7/9 inhibitor prodrug displaying potent anti-cancer effects against various cancer cell types. We performed in vitro and in vivo experiments to determine whether IB inhibits metastasis and eventually overcomes the poor drug response in TNBC. The result showed that IB inhibited the growth of TNBC cells by inducing caspase-mediated apoptosis and blocking metastasis by reducing MMP-9 expression in vitro. Concurrently, in vivo experiments using the metastasis model showed that IB inhibited metastasis of MDA-MB-231-Luc cells to the lung. Collectively, these results demonstrate that IB inhibited the growth of TNBC cells and blocked metastasis by regulating MMP-9 expression, suggesting a novel therapeutic agent for metastatic TNBC. Full article

(This article belongs to the Special Issue Breast Cancer, Metastatic Breast Cancer, Therapeutic Approaches, 2nd Edition)

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19 pages, 4457 KiB

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Modulated Electro-Hyperthermia Accelerates Tumor Delivery and Improves Anticancer Activity of Doxorubicin Encapsulated in Lyso-Thermosensitive Liposomes in 4T1-Tumor-Bearing Mice

by Kenan Aloss, Syeda Mahak Zahra Bokhari, Pedro Henrique Leroy Viana, Nino Giunashvili, Csaba András Schvarcz, Gábor Szénási, Dániel Bócsi, Zoltán Koós, Gert Storm, Zsuzsanna Miklós, Zoltán Benyó and Péter Hamar

Int. J. Mol. Sci. 2024, 25(6), 3101; https://doi.org/10.3390/ijms25063101 - 7 Mar 2024

Cited by 2 | Viewed by 1680

Abstract

Modulated electro-hyperthermia (mEHT) is an adjuvant cancer therapy that enables tumor-selective heating (+2.5 °C). In this study, we investigated whether mEHT accelerates the tumor-specific delivery of doxorubicin (DOX) from lyso-thermosensitive liposomal doxorubicin (LTLD) and improves its anticancer efficacy in mice bearing a triple-negative breast cancer cell line (4T1). The 4T1 cells were orthotopically injected into Balb/C mice, and mEHT was performed on days 9, 12, and 15 after the implantation. DOX, LTLD, or PEGylated liposomal DOX (PLD) were administered for comparison. The tumor size and DOX accumulation in the tumor were measured. The cleaved caspase-3 (cC3) and cell proliferation were evaluated by cC3 or Ki67 immunohistochemistry and Western blot. The LTLD+mEHT combination was more effective at inhibiting tumor growth than the free DOX and PLD, demonstrated by reductions in both the tumor volume and tumor weight. LTLD+mEHT resulted in the highest DOX accumulation in the tumor one hour after treatment. Tumor cell damage was associated with cC3 in the damaged area, and with a reduction in Ki67 in the living area. These changes were significantly the strongest in the LTLD+mEHT-treated tumors. The body weight loss was similar in all mice treated with any DOX formulation, suggesting no difference in toxicity. In conclusion, LTLD combined with mEHT represents a novel approach for DOX delivery into cancer tissue. Full article

(This article belongs to the Special Issue Breast Cancer, Metastatic Breast Cancer, Therapeutic Approaches, 2nd Edition)

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15 pages, 11448 KiB

Open AccessArticle

Loss of MXRA8 Delays Mammary Tumor Development and Impairs Metastasis

by Kaitlyn E. Simpson, Christina A. Staikos, Katrina L. Watson and Roger A. Moorehead

Int. J. Mol. Sci. 2023, 24(18), 13730; https://doi.org/10.3390/ijms241813730 - 6 Sep 2023

Cited by 1 | Viewed by 1696

Abstract

Matrix-remodeling-associated protein 8 or MXRA8 is a transmembrane protein that can bind arthritogenic alpha viruses like the Chikungunya virus and provide viral entry into cells. MXRA8 can also interact with integrin β3 and thus possibly regulate cell–cell interactions and binding to the extracellular matrix. While MXRA8 has been associated with reduced survival in patients with colorectal and renal clear cell cancers, the role of MXRA8 in breast cancer remains largely unexplored. Therefore, the aim of this research was to determine the role of MXRA8 in breast cancer by knocking out MXRA8 in the human triple-negative breast cancer cell line MDA-MB-231. The loss of MXRA8 reduced cell proliferation in vitro but had no effect on apoptosis or migration in cultured cells. However, the loss of MXRA8 significantly delayed tumor development and reduced metastatic dissemination to the lungs in a xenograft model. RNA sequencing identified three genes, ADMATS1, TIE1, and BMP2, whose expression were significantly reduced in MXRA8-knockout tumors compared to control tumors. MXRA8 staining of a human breast cancer tissue array revealed higher levels of MXRA8 in primary tumors and metastases of aggressive tumor subtypes (TNBC and HER2⁺) compared to less aggressive, ER⁺ breast cancers. Our findings demonstrate for the first time that MXRA8 regulates the progression of human TNBC possibly through influencing the interaction of tumor cells with their microenvironment. Full article

(This article belongs to the Special Issue Breast Cancer, Metastatic Breast Cancer, Therapeutic Approaches, 2nd Edition)

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Review

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30 pages, 2548 KiB

Open AccessReview

Unraveling the Role of Ras Homolog Enriched in Brain (Rheb1 and Rheb2): Bridging Neuronal Dynamics and Cancer Pathogenesis through Mechanistic Target of Rapamycin Signaling

by Mostafizur Rahman, Tuan Minh Nguyen, Gi Jeong Lee, Boram Kim, Mi Kyung Park and Chang Hoon Lee

Int. J. Mol. Sci. 2024, 25(3), 1489; https://doi.org/10.3390/ijms25031489 - 25 Jan 2024

Viewed by 1903

Abstract

Ras homolog enriched in brain (Rheb1 and Rheb2), small GTPases, play a crucial role in regulating neuronal activity and have gained attention for their implications in cancer development, particularly in breast cancer. This study delves into the intricate connection between the multifaceted functions of Rheb1 in neurons and cancer, with a specific focus on the mTOR pathway. It aims to elucidate Rheb1’s involvement in pivotal cellular processes such as proliferation, apoptosis resistance, migration, invasion, metastasis, and inflammatory responses while acknowledging that Rheb2 has not been extensively studied. Despite the recognized associations, a comprehensive understanding of the intricate interplay between Rheb1 and Rheb2 and their roles in both nerve and cancer remains elusive. This review consolidates current knowledge regarding the impact of Rheb1 on cancer hallmarks and explores the potential of Rheb1 as a therapeutic target in cancer treatment. It emphasizes the necessity for a deeper comprehension of the molecular mechanisms underlying Rheb1-mediated oncogenic processes, underscoring the existing gaps in our understanding. Additionally, the review highlights the exploration of Rheb1 inhibitors as a promising avenue for cancer therapy. By shedding light on the complicated roles between Rheb1/Rheb2 and cancer, this study provides valuable insights to the scientific community. These insights are instrumental in guiding the identification of novel targets and advancing the development of effective therapeutic strategies for treating cancer. Full article

(This article belongs to the Special Issue Breast Cancer, Metastatic Breast Cancer, Therapeutic Approaches, 2nd Edition)

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23 pages, 2323 KiB

Open AccessReview

CDKN1A/p21 in Breast Cancer: Part of the Problem, or Part of the Solution?

by Evangelos Manousakis, Clàudia Martinez Miralles, Maria Guimerà Esquerda and Roni H. G. Wright

Int. J. Mol. Sci. 2023, 24(24), 17488; https://doi.org/10.3390/ijms242417488 - 14 Dec 2023

Cited by 6 | Viewed by 3084

Abstract

Cyclin-dependent kinase inhibitor 1A (Cip1/Waf1/CDKN1A/p21) is a well-established protein, primarily recognised for its pivotal role in the cell cycle, where it induces cell cycle arrest by inhibiting the activity of cyclin-dependent kinases (CDKs). Over the years, extensive research has shed light on various additional mechanisms involving CDKN1A/p21, implicating it in processes such as apoptosis, DNA damage response (DDR), and the regulation of stem cell fate. Interestingly, p21 can function either as an oncogene or as a tumour suppressor in these contexts. Complicating matters further, the expression of CDKN1A/p21 is elevated in certain tumour types while downregulated in others. In this comprehensive review, we provide an overview of the multifaceted functions of CDKN1A/p21, present clinical data pertaining to cancer patients, and delve into potential strategies for targeting CDKN1A/p21 as a therapeutic approach to cancer. Manipulating CDKN1A/p21 shows great promise for therapy given its involvement in multiple cancer hallmarks, such as sustained cell proliferation, the renewal of cancer stem cells (CSCs), epithelial–mesenchymal transition (EMT), cell migration, and resistance to chemotherapy. Given the dual role of CDKN1A/p21 in these processes, a more in-depth understanding of its specific mechanisms of action and its regulatory network is imperative to establishing successful therapeutic interventions. Full article

(This article belongs to the Special Issue Breast Cancer, Metastatic Breast Cancer, Therapeutic Approaches, 2nd Edition)

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14 pages, 1133 KiB

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Semaphorins and Their Roles in Breast Cancer: Implications for Therapy Resistance

by Radhika Aiyappa-Maudsley, Louis F. V. McLoughlin and Thomas A. Hughes

Int. J. Mol. Sci. 2023, 24(17), 13093; https://doi.org/10.3390/ijms241713093 - 23 Aug 2023

Cited by 3 | Viewed by 1900

Abstract

Breast cancer is the most common cancer worldwide and a leading cause of cancer-related deaths in women. The clinical management of breast cancer is further complicated by the heterogeneous nature of the disease, which results in varying prognoses and treatment responses in patients. The semaphorins are a family of proteins with varied roles in development and homoeostasis. They are also expressed in a wide range of human cancers and are implicated as regulators of tumour growth, angiogenesis, metastasis and immune evasion. More recently, semaphorins have been implicated in drug resistance across a range of malignancies. In breast cancer, semaphorins are associated with resistance to endocrine therapy as well as breast cancer chemotherapeutic agents such as taxanes and anthracyclines. This review will focus on the semaphorins involved in breast cancer progression and their association with drug resistance. Full article

(This article belongs to the Special Issue Breast Cancer, Metastatic Breast Cancer, Therapeutic Approaches, 2nd Edition)

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