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Breast Cancer Mechanistic Insights and Targeted Therapies

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

Deadline for manuscript submissions: closed (10 January 2023) | Viewed by 28973

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Dr. Cornelia Braicu

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Research Center for Functional Genomics, Biomedicine and Translational Medicine, "Iuliu Hatieganu" University of Medicine and Pharmacy, 23 Marinescu Street, 400337 Cluj-Napoca, Romania
Interests: breast cancer; drug discovery; drug resistance; functional genomics; nutrigenomics; personalized medicine
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Dr. Ancuta Jurj

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Research Center for Functional Genomics, Biomedicine and Translational Medicine, "Iuliu Hatieganu" University of Medicine and Pharmacy, 23 Marinescu Street, 400337 Cluj-Napoca, Romania
Interests: extracellular vesicles; 3D cultures; drug resistance; breast cancer
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues

Breast cancer remains the most frequent cancer in women and at the same time is a highly heterogeneous disease, reflected on the different prognostic and treatment response rates.

Our special issue focus on the identification of biomarkers that underline the oncogenic signaling networks in breast cancer. A particular focus will be on the discovery of novel mechanistic insights for a personalized cancer treatment, and discovery and test of novel targeted therapies, preventing activation of drug resistance mechanisms for each individual breast cancer subtype.

The objective of the current Special Issue in IJMS is to publish original research papers and reviews of authors interested in addressing these challenges and to cover all the latest and outstanding development in the field of breast cancer.

Dr. Cornelia Braicu
Dr. Ancuta Jurj
Guest Editors

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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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Keywords

breast cancer
molecular mechanism
biomarkers
oncogenic signaling pathways
targeted therapies

Related Special Issue

Breast Cancer Mechanistic Insights and Targeted Therapies 2.0 in International Journal of Molecular Sciences (1 article)

Published Papers (11 papers)

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21 pages, 4626 KiB

Open AccessArticle

Antitumor Effect of Iscador on Breast Cancer Cell Lines with Different Metastatic Potential

by Bozhil Robev, Ivan Iliev, Iana Tsoneva, Albena Momchilova, Alexandrina Nesheva, Aneliya Kostadinova, Galya Staneva and Biliana Nikolova

Int. J. Mol. Sci. 2023, 24(6), 5247; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24065247 - 09 Mar 2023

Cited by 1 | Viewed by 2117

Abstract

Studies were performed for the first time on the effect of Iscador Qu and Iscador M on phototoxicity, cytotoxicity, antiproliferative activity, changes in ξ-potential of cells, membrane lipid order, actin cytoskeleton organization and migration on three breast cancer lines with different metastatic potential: MCF10A (control), MCF-7 (low metastatic) and MDA-MB231 (high metastatic) cells. The tested Iscador Qu and M did not show any phototoxicity. The antiproliferative effect of Iscador species appeared to be dose-dependent and was related to the metastatic potential of the tested cell lines. A higher selectivity index was obtained for Iscador Qu and M towards the low metastatic MCF-7 cell line compared to the high metastatic MDA-MB-231. Iscador Qu demonstrated higher selectivity for both cancer cell lines compared to Iscador M. The malignant cell lines exhibited a decrease in fibril number and thickness regardless of the type of Iscador used. The strongest effect on migration potential was observed for the low metastatic cancer cell line MCF-7 after Iscador treatment. Both Iscador species induced a slight increase in the percentage of cells in early apoptosis for the low and high metastatic cell lines, MCF-7 and MDA-MB-231, unlike control cells. Changes in the zeta potential and membrane lipid order were observed for the low metastatic MCF-7 cell line in contrast to the high metastatic MDA-MB-231 cells. The presented results reveal a higher potential of Iscador as an antitumor agent for the low metastatic cancer cell line MCF-7 compared to the high metastatic one. Iscador Qu appears to be more potent compared to Iscador M, but at this point, the exact mechanism of action is still unclear and needs further investigations. Full article

(This article belongs to the Special Issue Breast Cancer Mechanistic Insights and Targeted Therapies)

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16 pages, 4051 KiB

Open AccessArticle

Discovering the Biological Significance and Therapeutic Potential of miR-29b-3p in Triple-Negative Breast Cancer

by Ancuta Jurj, Oana Zanoaga, Lajos Raduly, Vlad Morhan, Zsofia Papi, Cristina Ciocan, Laura-Ancuta Pop, Ioana Berindan-Neagoe and Cornelia Braicu

Int. J. Mol. Sci. 2023, 24(5), 5048; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24055048 - 06 Mar 2023

Cited by 1 | Viewed by 1823

Abstract

The lack of estrogen or progesterone receptors and absence of HER2 amplification/overexpression in triple-negative breast cancer (TNBC) restricts therapeutic options used in clinical management. MicroRNAs (miRNAs) are small, non-coding transcripts which affect important cellular mechanisms by regulating gene expression at the post-transcriptional level. Among this class, attention was focused on miR-29b-3p with a high profile in TNBC and correlated with the overall survival rates, as TCGA data revealed. This study aims to investigate the implication of the miR-29b-3p inhibitor in TNBC cell lines by identifying a potential therapeutic transcript, improving the clinical outcomes of this disease. The experiments were performed on two TNBC cell lines (MDA-MB-231 and BT549) as in vitro models. An established dose of 50 nM was used for all functional assays performed on the miR-29b-3p inhibitor. A decreased level of miR-29b-3p determined a significant reduction in cell proliferation and colony-forming capacity. At the same time, the changes occurring at the molecular and cellular levels were highlighted. We observed that, when inhibiting the expression level of miR-29b-3p, processes such as apoptosis and autophagy were activated. Further, microarray data revealed that the miRNA expression pattern was altered after miR-29b-3p inhibition, pointing out 8 overexpressed and 11 downregulated miRNAs specific for BT549 cells and 33 upregulated and 10 downregulated miRNAs that were specific for MDA-MB-231 cells. As a common signature for both cell lines, three transcripts were observed, two downregulated, miR-29b-3p and miR-29a, and one upregulated, miR-1229-5p. According to DIANA miRPath, the main predicted targets are related to ECM (extracellular matrix) receptor interaction and TP53 signaling. An additional validation step through qRT-PCR was performed, which showed an upregulation of MCL1 and TGFB1. By inhibiting the expression level of miR-29b-3p, it was shown that complex regulatory pathways targeted this transcript in TNBC cells. Full article

(This article belongs to the Special Issue Breast Cancer Mechanistic Insights and Targeted Therapies)

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21 pages, 4643 KiB

Open AccessArticle

“Pulsed Hypoxia” Gradually Reprograms Breast Cancer Fibroblasts into Pro-Tumorigenic Cells via Mesenchymal–Epithelial Transition

by Anna Nushtaeva, Mikhail Ermakov, Maria Abdurakhmanova, Olga Troitskaya, Tatyana Belovezhets, Mikhail Varlamov, Tatyana Gayner, Vladimir Richter and Olga Koval

Int. J. Mol. Sci. 2023, 24(3), 2494; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24032494 - 27 Jan 2023

Cited by 7 | Viewed by 1813

Abstract

Hypoxia arises in most growing solid tumors and can lead to pleotropic effects that potentially increase tumor aggressiveness and resistance to therapy through regulation of the expression of genes associated with the epithelial–mesenchymal transition (EMT) and mesenchymal–epithelial transition (MET). The main goal of the current work was to obtain and investigate the intermediate phenotype of tumor cells undergoing the hypoxia-dependent transition from fibroblast to epithelial morphology. Primary breast cancer fibroblasts BrC4f, being cancer-associated fibroblasts, were subjected to one or two rounds of “pulsed hypoxia” (PH). PH induced transformation of fibroblast-shaped cells to semi-epithelial cells. Western blot analysis, fluorescent microscopy and flow cytometry of transformed cells demonstrated the decrease in the mesenchymal markers vimentin and N-cad and an increase in the epithelial marker E-cad. These cells kept mesenchymal markers αSMA and S100A4 and high ALDH activity. Real-time PCR data of the cells after one (BrC4f_Hyp1) and two (BrC4f_Hyp2) rounds of PH showed consistent up-regulation of TWIST1 gene as an early response and ZEB1/2 and SLUG transcriptional activity as a subsequent response. Reversion of BrC4f_Hyp2 cells to normoxia conditions converted them to epithelial-like cells (BrC4e) with decreased expression of EMT genes and up-regulation of MET-related OVOL2 and c-MYC genes. Transplantation of BrC4f and BrC4f_Hyp2 cells into SCID mice showed the acceleration of tumor growth up to 61.6% for BrC4f_Hyp2 cells. To summarize, rounds of PH imitate the MET process of tumorigenesis in which cancer-associated fibroblasts pass through intermediate stages and become more aggressive epithelial-like tumor cells. Full article

(This article belongs to the Special Issue Breast Cancer Mechanistic Insights and Targeted Therapies)

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15 pages, 3161 KiB

Open AccessArticle

PLA2G7/PAF-AH as Potential Negative Regulator of the Wnt Signaling Pathway Mediates Protective Effects in BRCA1 Mutant Breast Cancer

by Yue Liao, Susann Badmann, Fabian Kraus, Nicole Elisabeth Topalov, Doris Mayr, Thomas Kolben, Anna Hester, Susanne Beyer, Sven Mahner, Udo Jeschke, Fabian Trillsch, Bastian Czogalla and Alexander Burges

Int. J. Mol. Sci. 2023, 24(1), 882; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24010882 - 03 Jan 2023

Cited by 2 | Viewed by 2438

Abstract

Past studies have confirmed that aberrant activation of the Wnt/β-catenin signaling is associated with tumorigenesis and metastasis in breast cancer, while the role of platelet-activating factor acetylhydrolase (PLA2G7/PAF-AH) in this signaling pathway remains unclear. In this study, we analyze the functional impact of PAF-AH on BRCA1 mutant breast cancer and explore its relationship to the Wnt signaling pathway. By performing immunohistochemistry, PAF-AH expression and β-catenin expression were examined in both BRCA1 WT and BRCA1 mutant breast cancer specimens. The BRCA1 mutant breast cancer cell line HCC1937 was used for in vitro experiments to assess the impact of PAF-AH on cellular functions. The intracellular distribution of β-catenin depending on PLA2G7/PAF-AH expression was investigated by immunocytochemistry. Significantly higher nuclear expression levels of PAF-AH were found in BRCA1 mutant tissue specimens than in BRCA1 WT samples. Cell viability, proliferation, and the motility rate of HCC1937 were significantly enhanced after PLA2G7 silencing, which indicated a protective role of PAF-AH in breast cancer. Nuclear PAF-AH expressed correlatedly with membranous β-catenin. PLA2G7 silencing provoked the β-catenin translocation from the membrane to the nucleus and activated Wnt signaling downstream genes. Our data showed a protective effect of high PAF-AH expression in BRCA1 mutant breast cancer. PAF-AH may achieve its protective effect by negatively regulating the Wnt pathway. In conclusion, our research sheds new light on the regulatory pathways in BRCA1 mutant breast cancer. Full article

(This article belongs to the Special Issue Breast Cancer Mechanistic Insights and Targeted Therapies)

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21 pages, 5244 KiB

Open AccessArticle

Intratumoral Treatment with 5-Androstene-3β, 17α-Diol Reduces Tumor Size and Lung Metastasis in a Triple-Negative Experimental Model of Breast Cancer

by Rocío Alejandra Ruiz Manzano, Karen Elizabeth Nava-Castro, Margarita Isabel Palacios-Arreola, Rosalía Hernández-Cervantes, Víctor Hugo Del Río-Araiza, Mariana Segovia-Mendoza, Armando Pérez-Torres, Manuel Iván Girón-Pérez and Jorge Morales-Montor

Int. J. Mol. Sci. 2022, 23(19), 11944; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231911944 - 08 Oct 2022

Viewed by 1529

Abstract

Breast cancer treatment failure is related to low response rates, high costs, and long-term toxicities. Thus, it is necessary to find less toxic, cheaper, and more effective treatments. In situ administration ensures drug delivery to tumor cells and decreases systemic toxic effects. The androstene-3β, 17α-diol (α-AED) reduces breast tumor cell proliferation and is an ideal candidate to treat mammary tumors. This study aims to identify the in vitro and in vivo effects of α-AED on a triple-negative mammary tumor model. An in vitro biphasic steroid effect was observed in mouse and human mammary tumor cells treated with α-AED. In this sense, cells treated with higher doses (100 and 200 μM) showed an antiproliferative effect. The α-AED administrated intratumorally reduced average tumor weight and increased the percentage of natural killer cells (NK), plasmatic, and plasmablast cells in mice tumors. Of note, VEGF levels in all α-AED-treated tumors was lower than in the control and vehicle groups. The tumor in situ increased response was reflected systemically by higher anti-4T1 IgG concentration in serum from α-AED-treated mice, but no other associated systemic changes were detected. The reduction in tumor size for the local injection of α-AED is associated with the anti-proliferative effect of this steroid, and the lower local levels of VEGF may be related to the imperceptible macroscopic metastasis in α-AED-treated mice. The above suggests that α-AED may be used in clinical studies to prove its efficacy as an alternative breast tumor treatment or in conjunction with already established therapies. Full article

(This article belongs to the Special Issue Breast Cancer Mechanistic Insights and Targeted Therapies)

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27 pages, 7197 KiB

Open AccessArticle

Pro-Apoptotic and Anti-Invasive Properties Underscore the Tumor-Suppressing Impact of Myoglobin on a Subset of Human Breast Cancer Cells

by Mostafa A. Aboouf, Julia Armbruster, Markus Thiersch, Franco Guscetti, Glen Kristiansen, Peter Schraml, Anne Bicker, Ruben Petry, Thomas Hankeln, Max Gassmann and Thomas A. Gorr

Int. J. Mol. Sci. 2022, 23(19), 11483; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231911483 - 29 Sep 2022

Cited by 2 | Viewed by 2030

Abstract

The expression of myoglobin (MB), well known as the oxygen storage and transport protein of myocytes, is a novel hallmark of the luminal subtype in breast cancer patients and correlates with better prognosis. The mechanisms by which MB impacts mammary tumorigenesis are hitherto unclear. We aimed to unravel this role by using CRISPR/Cas9 technology to generate MB-deficient clones of MCF7 and SKBR3 breast cancer cell lines and subsequently characterize them by transcriptomics plus molecular and functional analyses. As main findings, loss of MB at normoxia upregulated the expression of cell cyclins and increased cell survival, while it prevented apoptosis in MCF7 cells. Additionally, MB-deficient cells were less sensitive to doxorubicin but not ionizing radiation. Under hypoxia, the loss of MB enhanced the partial epithelial to mesenchymal transition, thus, augmenting the migratory and invasive behavior of cells. Notably, in human invasive mammary ductal carcinoma tissues, MB and apoptotic marker levels were positively correlated. In addition, MB protein expression in invasive ductal carcinomas was associated with a positive prognostic value, independent of the known tumor suppressor p53. In conclusion, we provide multiple lines of evidence that endogenous MB in cancer cells by itself exerts novel tumor-suppressive roles through which it can reduce cancer malignancy. Full article

(This article belongs to the Special Issue Breast Cancer Mechanistic Insights and Targeted Therapies)

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17 pages, 7745 KiB

Open AccessArticle

Arachidin-1, a Prenylated Stilbenoid from Peanut, Induces Apoptosis in Triple-Negative Breast Cancer Cells

by Sepideh Mohammadhosseinpour, Linh-Chi Ho, Lingling Fang, Jianfeng Xu and Fabricio Medina-Bolivar

Int. J. Mol. Sci. 2022, 23(3), 1139; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23031139 - 20 Jan 2022

Cited by 9 | Viewed by 3862

Abstract

Triple-negative breast cancer (TNBC) is unresponsive to typical hormonal treatments, causing it to be one of the deadliest forms of breast cancer. Investigating alternative therapies to increase survival rates for this disease is essential. The goal of this study was to assess cytotoxicity and apoptosis mechanisms of prenylated stilbenoids in TNBC cells. The prenylated stilbenoids arachidin-1 (A-1) and arachidin-3 (A-3) are analogs of resveratrol (RES) produced in peanut upon biotic stress. The anticancer activity of A-1 and A-3 isolated from peanut hairy root cultures was determined in TNBC cell lines MDA-MB-231 and MDA-MB-436. After 24 h of treatment, A-1 exhibited higher cytotoxicity than A-3 and RES with approximately 11-fold and six-fold lower IC₅₀, respectively, in MDA-MB-231 cells, and nine-fold and eight-fold lower IC₅₀, respectively, in MDA-MB-436 cells. A-1 did not show significant cytotoxicity in the non-cancerous cell line MCF-10A. While A-1 blocked cell division in G2-M phases in the TNBC cells, it did not affect cell division in MCF-10A cells. Furthermore, A-1 induced caspase-dependent apoptosis through the intrinsic pathway by activating caspase-9 and PARP cleavage, and inhibiting survivin. In conclusion, A-1 merits further research as a potential lead molecule for the treatment of TNBC. Full article

(This article belongs to the Special Issue Breast Cancer Mechanistic Insights and Targeted Therapies)

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16 pages, 4645 KiB

Open AccessArticle

Soluble CD146 as a Potential Target for Preventing Triple Negative Breast Cancer MDA-MB-231 Cell Growth and Dissemination

by Akshita Sharma, Ahmad Joshkon, Aymen Ladjimi, Waël Traboulsi, Richard Bachelier, Stéphane Robert, Alexandrine Foucault-Bertaud, Aurélie S. Leroyer, Nathalie Bardin, Indumathi Somasundaram and Marcel Blot-Chabaud

Int. J. Mol. Sci. 2022, 23(2), 974; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23020974 - 17 Jan 2022

Cited by 3 | Viewed by 2722

Abstract

Background: Triple Negative Breast Cancers (TNBC) are the most aggressive breast cancers and lead to poor prognoses. This is due to a high resistance to therapies, mainly because of the presence of Cancer Stem Cells (CSCs). Plasticity, a feature of CSCs, is acquired through the Epithelial to Mesenchymal Transition (EMT), a process that has been recently shown to be regulated by a key molecule, CD146. Of interest, CD146 is over-expressed in TNBC. Methods: The MDA-MB-231 TNBC cell line was used as a model to study the role of CD146 and its secreted soluble form (sCD146) in the development and dissemination of TNBC using in vitro and in vivo studies. Results: High expression of CD146 in a majority of MDA-MB-231 cells leads to an increased secretion of sCD146 that up-regulates the expression of EMT and CSC markers on the cells. These effects can be blocked with a specific anti-sCD146 antibody, M2J-1 mAb. M2J-1 mAb was able to reduce tumour development and dissemination in a model of cells xenografted in nude mice and an experimental model of metastasis, respectively, in part through its effects on CSC. Conclusion: We propose that M2J-1 mAb could be used as an additional therapeutic approach to fight TNBC. Full article

(This article belongs to the Special Issue Breast Cancer Mechanistic Insights and Targeted Therapies)

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13 pages, 2502 KiB

Open AccessArticle

G9a Knockdown Suppresses Cancer Aggressiveness by Facilitating Smad Protein Phosphorylation through Increasing BMP5 Expression in Luminal A Type Breast Cancer

by Yunho Jin, Shinji Park, Soon-Yong Park, Chae-Young Lee, Da-Young Eum, Jae-Woong Shim, Si-Ho Choi, Yoo-Jin Choi, Seong-Joon Park and Kyu Heo

Int. J. Mol. Sci. 2022, 23(2), 589; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23020589 - 06 Jan 2022

Cited by 11 | Viewed by 1820

Abstract

Epigenetic abnormalities affect tumor progression, as well as gene expression and function. Among the diverse epigenetic modulators, the histone methyltransferase G9a has been focused on due to its role in accelerating tumorigenesis and metastasis. Although epigenetic dysregulation is closely related to tumor progression, reports regarding the relationship between G9a and its possible downstream factors regulating breast tumor growth are scarce. Therefore, we aimed to verify the role of G9a and its presumable downstream regulators during malignant progression of breast cancer. G9a-depleted MCF7 and T47D breast cancer cells exhibited suppressed motility, including migration and invasion, and an improved response to ionizing radiation. To identify the possible key factors underlying these effects, microarray analysis was performed, and a TGF-β superfamily member, BMP5, was selected as a prominent target gene. It was found that BMP5 expression was markedly increased by G9a knockdown. Moreover, reduction in the migration/invasion ability of MCF7 and T47D breast cancer cells was induced by BMP5. Interestingly, a G9a-depletion-mediated increase in BMP5 expression induced the phosphorylation of Smad proteins, which are the intracellular signaling mediators of BMP5. Accordingly, we concluded that the observed antitumor effects may be based on the G9a-depletion-mediated increase in BMP5 expression and the consequent facilitation of Smad protein phosphorylation. Full article

(This article belongs to the Special Issue Breast Cancer Mechanistic Insights and Targeted Therapies)

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19 pages, 4764 KiB

Open AccessArticle

Targeting Lipocalin-2 in Inflammatory Breast Cancer Cells with Small Interference RNA and Small Molecule Inhibitors

by Ginette S. Santiago-Sánchez, Ricardo Noriega-Rivera, Eliud Hernández-O’Farrill, Fatma Valiyeva, Blanca Quiñones-Diaz, Emilly S. Villodre, Bisrat G. Debeb, Andrea Rosado-Albacarys and Pablo E. Vivas-Mejía

Int. J. Mol. Sci. 2021, 22(16), 8581; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22168581 - 10 Aug 2021

Cited by 10 | Viewed by 3391

Abstract

Inflammatory Breast Cancer (IBC) is an aggressive form of invasive breast cancer, highly metastatic, representing 2–4% of all breast cancer cases in the United States. Despite its rare nature, IBC is responsible for 7–10% of all breast cancer deaths, with a 5-year survival rate of 40%. Thus, targeted and effective therapies against IBC are needed. Here, we proposed Lipocalin-2 (LCN2)—a secreted glycoprotein aberrantly abundant in different cancers—as a plausible target for IBC. In immunoblotting, we observed higher LCN2 protein levels in IBC cells than non-IBC cells, where the LCN2 levels were almost undetectable. We assessed the biological effects of targeting LCN2 in IBC cells with small interference RNAs (siRNAs) and small molecule inhibitors. siRNA-mediated LCN2 silencing in IBC cells significantly reduced cell proliferation, viability, migration, and invasion. Furthermore, LCN2 silencing promoted apoptosis and arrested the cell cycle progression in the G0/G1 to S phase transition. We used in silico analysis with a library of 25,000 compounds to identify potential LCN2 inhibitors, and four out of sixteen selected compounds significantly decreased cell proliferation, cell viability, and the AKT phosphorylation levels in SUM149 cells. Moreover, ectopically expressing LCN2 MCF7 cells, treated with two potential LCN2 inhibitors (ZINC00784494 and ZINC00640089) showed a significant decrease in cell proliferation. Our findings suggest LCN2 as a promising target for IBC treatment using siRNA and small molecule inhibitors. Full article

(This article belongs to the Special Issue Breast Cancer Mechanistic Insights and Targeted Therapies)

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Review

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27 pages, 2364 KiB

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The Variety of 3D Breast Cancer Models for the Study of Tumor Physiology and Drug Screening

by Eleonore Fröhlich

Int. J. Mol. Sci. 2023, 24(8), 7116; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24087116 - 12 Apr 2023

Cited by 6 | Viewed by 3732

Abstract

Breast cancer is the most common cancer in women and responsible for multiple deaths worldwide. 3D cancer models enable a better representation of tumor physiology than the conventional 2D cultures. This review summarizes the important components of physiologically relevant 3D models and describes the spectrum of 3D breast cancer models, e.g., spheroids, organoids, breast cancer on a chip and bioprinted tissues. The generation of spheroids is relatively standardized and easy to perform. Microfluidic systems allow control over the environment and the inclusion of sensors and can be combined with spheroids or bioprinted models. The strength of bioprinting relies on the spatial control of the cells and the modulation of the extracellular matrix. Except for the predominant use of breast cancer cell lines, the models differ in stromal cell composition, matrices and fluid flow. Organoids are most appropriate for personalized treatment, but all technologies can mimic most aspects of breast cancer physiology. Fetal bovine serum as a culture supplement and Matrigel as a scaffold limit the reproducibility and standardization of the listed 3D models. The integration of adipocytes is needed because they possess an important role in breast cancer. Full article

(This article belongs to the Special Issue Breast Cancer Mechanistic Insights and Targeted Therapies)

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