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21 pages, 4729 KiB

Open AccessArticle

Bicalutamide Enhances Conventional Chemotherapy in In Vitro and In Vivo Assays Using Human and Canine Inflammatory Mammary Cancer Cell Lines

by Belen Crespo, Juan Carlos Illera, Gema Silvan, Paula Lopez-Plaza, María Herrera de la Muela, Miriam de la Puente Yague, Cristina Diaz del Arco, Paloma Jimena de Andrés, Maria Jose Illera and Sara Caceres

Int. J. Mol. Sci. 2024, 25(14), 7923; https://doi.org/10.3390/ijms25147923 - 19 Jul 2024

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Abstract

Human inflammatory breast cancer (IBC) and canine inflammatory mammary cancer (IMC) are highly aggressive neoplastic diseases that share numerous characteristics. In IBC and IMC, chemotherapy produces a limited pathological response and anti-androgen therapies have been of interest for breast cancer treatment. Therefore, the [...] Read more.

Human inflammatory breast cancer (IBC) and canine inflammatory mammary cancer (IMC) are highly aggressive neoplastic diseases that share numerous characteristics. In IBC and IMC, chemotherapy produces a limited pathological response and anti-androgen therapies have been of interest for breast cancer treatment. Therefore, the aim was to evaluate the effect of a therapy based on bicalutamide, a non-steroidal anti-androgen, with doxorubicin and docetaxel chemotherapy on cell proliferation, migration, tumor growth, and steroid-hormone secretion. An IMC-TN cell line, IPC-366, and an IBC-TN cell line, SUM149, were used. In vitro assays revealed that SUM149 exhibited greater sensitivity, reducing cell viability and migration with all tested drugs. In contrast, IPC-366 exhibited only significant in vitro reductions with docetaxel as a single agent or in different combinations. Decreased estrogen levels reduced in vitro tumor growth in both IMC and IBC. Curiously, doxorubicin resulted in low efficacy, especially in IMC. In addition, all drugs reduced the tumor volume in IBC and IMC by increasing intratumoral testosterone (T) levels, which have been related with reduced tumor progression. In conclusion, the addition of bicalutamide to doxorubicin and docetaxel combinations may represent a potential treatment for IMC and IBC. Full article

(This article belongs to the Special Issue Molecular Mechanisms and New Therapies for Breast Cancer)

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19 pages, 2918 KiB

Open AccessArticle

Expression Profiles of Dopamine-Related Genes and miRNAs Regulating Their Expression in Breast Cancer

by Tomasz Sirek, Agata Sirek, Przemysław Borawski, Izabella Ryguła, Katarzyna Król-Jatręga, Marcin Opławski, Dariusz Boroń, Michał Chalcarz, Piotr Ossowski, Konrad Dziobek, Nikola Zmarzły, Kacper Boroń, Patrycja Mickiewicz and Beniamin Oskar Grabarek

Int. J. Mol. Sci. 2024, 25(12), 6546; https://doi.org/10.3390/ijms25126546 - 14 Jun 2024

Cited by 1 | Viewed by 1296

Abstract

This study aimed to assess the expression profile of messenger RNA (mRNA) and microRNA (miRNA) related to the dopaminergic system in five types of breast cancer in Polish women. Patients with five breast cancer subtypes were included in the study: luminal A ( [...] Read more.

This study aimed to assess the expression profile of messenger RNA (mRNA) and microRNA (miRNA) related to the dopaminergic system in five types of breast cancer in Polish women. Patients with five breast cancer subtypes were included in the study: luminal A (n = 130), luminal B (n = 196, including HER2−, n = 100; HER2+, n = 96), HER2+ (n = 36), and TNBC (n = 43); they underwent surgery, during which tumor tissue was removed along with a margin of healthy tissue (control material). The molecular analysis included a microarray profile of mRNAs and miRNAs associated with the dopaminergic system, a real-time polymerase chain reaction preceded by reverse transcription for selected genes, and determinations of their concentration using enzyme-linked immunosorbent assay (ELISA). The conducted statistical analysis showed that five mRNAs statistically significantly differentiated breast cancer sections regardless of subtype compared to control samples; these were dopamine receptor 2 (DRD2), dopamine receptor 3 (DRD3), dopamine receptor 25 (DRD5), transforming growth factor beta 2 (TGF-β-2), and caveolin 2 (CAV2). The predicted analysis showed that hsa-miR-141-3p can regulate the expression of DRD2 and TGF-β-2, whereas hsa-miR-4441 is potentially engaged in the expression regulation of DRD3 and DRD5. In addition, the expression pattern of DRD5 mRNA can also be regulated by has-miR-16-5p. The overexpression of DRD2 and DRD3, with concomitant silencing of DRD5 expression, confirms the presence of dopaminergic abnormalities in breast cancer patients. Moreover, these abnormalities may be the result of miR-141-3P, miR-16-5p, and miR-4441 activity, regulating proliferation or metastasis. Full article

(This article belongs to the Special Issue Molecular Mechanisms and New Therapies for Breast Cancer)

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16 pages, 3652 KiB

Open AccessArticle

Exploring CDKN1A Upregulation Mechanisms: Insights into Cell Cycle Arrest Induced by NC2603 Curcumin Analog in MCF-7 Breast Cancer Cells

by Felipe Garcia Nishimura, Beatriz Borsani Sampaio, Tatiana Takahasi Komoto, Wanessa Julia da Silva, Mariana Mezencio Gregório da Costa, Gabriela Inforçatti Haddad, Kamila Chagas Peronni, Adriane Feijó Evangelista, Mohammad Hossain, Jonathan R. Dimmock, Brian Bandy, Rene Oliveira Beleboni, Mozart Marins and Ana Lucia Fachin

Int. J. Mol. Sci. 2024, 25(9), 4989; https://doi.org/10.3390/ijms25094989 - 3 May 2024

Cited by 2 | Viewed by 1437

Abstract

Breast cancer stands out as one of the most prevalent malignancies worldwide, necessitating a nuanced understanding of its molecular underpinnings for effective treatment. Hormone receptors in breast cancer cells substantially influence treatment strategies, dictating therapeutic approaches in clinical settings, serving as a guide [...] Read more.

Breast cancer stands out as one of the most prevalent malignancies worldwide, necessitating a nuanced understanding of its molecular underpinnings for effective treatment. Hormone receptors in breast cancer cells substantially influence treatment strategies, dictating therapeutic approaches in clinical settings, serving as a guide for drug development, and aiming to enhance treatment specificity and efficacy. Natural compounds, such as curcumin, offer a diverse array of chemical structures with promising therapeutic potential. Despite curcumin’s benefits, challenges like poor solubility and rapid metabolism have spurred the exploration of analogs. Here, we evaluated the efficacy of the curcumin analog NC2603 to induce cell cycle arrest in MCF-7 breast cancer cells and explored its molecular mechanisms. Our findings reveal potent inhibition of cell viability (IC50 = 5.6 μM) and greater specificity than doxorubicin toward MCF-7 vs. non-cancer HaCaT cells. Transcriptome analysis identified 12,055 modulated genes, most notably upregulation of GADD45A and downregulation of ESR1, implicating CDKN1A-mediated regulation of proliferation and cell cycle genes. We hypothesize that the curcumin analog by inducing GADD45A expression and repressing ESR1, triggers the expression of CDKN1A, which in turn downregulates the expression of many important genes of proliferation and the cell cycle. These insights advance our understanding of curcumin analogs’ therapeutic potential, highlighting not just their role in treatment, but also the molecular pathways involved in their activity toward breast cancer cells. Full article

(This article belongs to the Special Issue Molecular Mechanisms and New Therapies for Breast Cancer)

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15 pages, 18133 KiB

Open AccessArticle

Combination Therapy with a TLR7 Agonist and a BRD4 Inhibitor Suppresses Tumor Growth via Enhanced Immunomodulation

by Yong-Si Liu, Jia-Xin Wang, Guang-Yi Jin, Ming-Hao Hu and Xiao-Dong Wang

Int. J. Mol. Sci. 2024, 25(1), 663; https://doi.org/10.3390/ijms25010663 - 4 Jan 2024

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Abstract

JQ-1 is a typical BRD4 inhibitor with the ability to directly fight tumor cells and evoke antitumor immunity via reducing the expression of PD-L1. However, problems arise with the development of JQ-1 in clinical trials, such as marked lymphoid and hematopoietic toxicity, leading [...] Read more.

JQ-1 is a typical BRD4 inhibitor with the ability to directly fight tumor cells and evoke antitumor immunity via reducing the expression of PD-L1. However, problems arise with the development of JQ-1 in clinical trials, such as marked lymphoid and hematopoietic toxicity, leading to the investigation of combination therapy. SZU-101 is a TLR7 agonist designed and synthesized by our group with potent immunostimulatory activity. Therefore, we hypothesized that combination therapy of SZU-101 and JQ-1 would target innate immunity and adaptive immunity simultaneously, to achieve a better antitumor efficacy than monotherapy. In this study, the repressive effects of the combination administration on tumor growth and metastasis were demonstrated in both murine breast cancer and melanoma models. In 4T1 tumor-bearing mice, i.t. treatment with SZU-101 in combination with i.p. treatment with JQ-1 suppressed the growth of tumors at both injected and uninjected sites. Combination therapy increased M1/M2 ratio in TAMs, decreased PD-L1 expression and promoted the recruitment of activated CD8⁺ T cells in the TME. In summary, the improved therapeutic efficacy of the novel combination therapy appears to be feasible for the treatment of a diversity of cancers. Full article

(This article belongs to the Special Issue Molecular Mechanisms and New Therapies for Breast Cancer)

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20 pages, 46677 KiB

Open AccessArticle

Therapeutic Peptide RF16 Derived from CXCL8 Inhibits MDA-MB-231 Cell Invasion and Metastasis

by Chun-Ming Chang, Chun-Chun Chang, Ho Yin Pekkle Lam, Shih-Yi Peng, Yi-Hsuan Lai, Bi-Da Hsiang, Yu-Yi Liao, Hao-Jen Hsu and Shinn-Jong Jiang

Int. J. Mol. Sci. 2023, 24(18), 14029; https://doi.org/10.3390/ijms241814029 - 13 Sep 2023

Cited by 2 | Viewed by 1601

Abstract

Interleukin (IL)-8 plays a vital role in regulating inflammation and breast cancer formation by activating CXCR1/2. We previously designed an antagonist peptide, (RF16), to inhibits the activation of downstream signaling pathways by competing with IL-8 in binding to CXCR1/2, thereby inhibiting IL-8-induced chemoattractant [...] Read more.

Interleukin (IL)-8 plays a vital role in regulating inflammation and breast cancer formation by activating CXCR1/2. We previously designed an antagonist peptide, (RF16), to inhibits the activation of downstream signaling pathways by competing with IL-8 in binding to CXCR1/2, thereby inhibiting IL-8-induced chemoattractant monocyte binding. To evaluate the effect of the RF16 peptide on breast cancer progression, triple-negative MDA-MB-231 and ER-positive MCF-7 breast cancer cells were used to investigate whether RF16 can inhibit the IL-8-induced breast cancer metastasis. Using growth, proliferation, and invasiveness assays, the results revealed that RF16 reduced cell proliferation, migration, and invasiveness in MDA-MB-231 cells. The RF16 peptide also regulated the protein and mRNA expressions of epithelial–mesenchymal transition (EMT) markers in IL-8-stimulated MDA-MB-231 cells. It also inhibited downstream IL-8 signaling and the IL-8-induced inflammatory response via the mitogen-activated protein kinase (MAPK) and Phosphoinositide 3-kinase (PI3K) pathways. In the xenograft tumor mouse model, RF16 synergistically reinforces the antitumor efficacy of docetaxel by improving mouse survival and retarding tumor growth. Our results indicate that RF16 significantly inhibited IL-8-stimulated cell growth, migration, and invasion in MDA-MB-231 breast cancer cells by blocking the activation of p38 and AKT cascades. It indicated that the RF16 peptide may serve as a new supplementary drug for breast cancer. Full article

(This article belongs to the Special Issue Molecular Mechanisms and New Therapies for Breast Cancer)

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12 pages, 1657 KiB

Open AccessArticle

Survivin Expression in Luminal Breast Cancer and Adjacent Normal Tissue for Immuno-Oncology Applications

by Sharon Wright, Scott R. Burkholz, Cathy Zelinsky, Connor Wittman, Richard T. Carback, Paul E. Harris, Tikoes Blankenberg, Charles V. Herst and Reid M. Rubsamen

Int. J. Mol. Sci. 2023, 24(14), 11827; https://doi.org/10.3390/ijms241411827 - 23 Jul 2023

Cited by 4 | Viewed by 1930

Abstract

Survivin (BIRC5) is a tumor-associated antigen (TAA) overexpressed in various tumors but present at low to undetectable levels in normal tissue. Survivin is known to have a high expression in breast cancer (e.g., Ductal Carcinoma in situ (DCIS) and triple negative breast cancer). [...] Read more.

Survivin (BIRC5) is a tumor-associated antigen (TAA) overexpressed in various tumors but present at low to undetectable levels in normal tissue. Survivin is known to have a high expression in breast cancer (e.g., Ductal Carcinoma in situ (DCIS) and triple negative breast cancer). Previous studies have not compared survivin expression levels in DCIS tumor samples to levels in adjacent, normal breast tissue from the same patient. To ensure the effective use of survivin as a target for T cell immunotherapy of breast cancer, it is essential to ascertain the varying levels of survivin expression between DCIS tumor tissue samples and the adjacent normal breast tissue taken from the same patient simultaneously. Next-generation sequencing of RNA (RNA-seq) in normal breast tissue and tumor breast tissue from five women presenting with DCIS for lumpectomy was used to identify sequence variation and expression levels of survivin. The identity of both tumor and adjacent normal tissue samples were corroborated by histopathology. Survivin was overexpressed in human breast tissue tumor samples relative to the corresponding adjacent human normal breast tissue. Wild-type survivin transcripts were the predominant species identified in all tumor tissue sequenced. This study demonstrates upregulated expression of wild type survivin in DCIS tumor tissue versus normal breast tissue taken from the same patient at the same time, and provides evidence that developing selective cytotoxic T lymphocyte (CTL) immunotherapy for DCIS targeting survivin warrants further study. Full article

(This article belongs to the Special Issue Molecular Mechanisms and New Therapies for Breast Cancer)

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Review

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29 pages, 2147 KiB

Open AccessReview

The Use of Patient-Derived Organoids in the Study of Molecular Metabolic Adaptation in Breast Cancer

by Natalija Glibetic, Scott Bowman, Tia Skaggs and Michael Weichhaus

Int. J. Mol. Sci. 2024, 25(19), 10503; https://doi.org/10.3390/ijms251910503 - 29 Sep 2024

Viewed by 1766

Abstract

Around 13% of women will likely develop breast cancer during their lifetime. Advances in cancer metabolism research have identified a range of metabolic reprogramming events, such as altered glucose and amino acid uptake, increased reliance on glycolysis, and interactions with the tumor microenvironment [...] Read more.

Around 13% of women will likely develop breast cancer during their lifetime. Advances in cancer metabolism research have identified a range of metabolic reprogramming events, such as altered glucose and amino acid uptake, increased reliance on glycolysis, and interactions with the tumor microenvironment (TME), all of which present new opportunities for targeted therapies. However, studying these metabolic networks is challenging in traditional 2D cell cultures, which often fail to replicate the three-dimensional architecture and dynamic interactions of real tumors. To address this, organoid models have emerged as powerful tools. Tumor organoids are 3D cultures, often derived from patient tissue, that more accurately mimic the structural and functional properties of actual tumor tissues in vivo, offering a more realistic model for investigating cancer metabolism. This review explores the unique metabolic adaptations of breast cancer and discusses how organoid models can provide deeper insights into these processes. We evaluate the most advanced tools for studying cancer metabolism in three-dimensional culture models, including optical metabolic imaging (OMI), matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI), and recent advances in conventional techniques applied to 3D cultures. Finally, we explore the progress made in identifying and targeting potential therapeutic targets in breast cancer metabolism. Full article

(This article belongs to the Special Issue Molecular Mechanisms and New Therapies for Breast Cancer)

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20 pages, 1811 KiB

Open AccessReview

Therapeutic Potential of 1,8-Dihydroanthraquinone Derivatives for Breast Cancer

by Estera Okon, Katarzyna Gaweł-Bęben, Agata Jarzab, Wojciech Koch, Wirginia Kukula-Koch and Anna Wawruszak

Int. J. Mol. Sci. 2023, 24(21), 15789; https://doi.org/10.3390/ijms242115789 - 31 Oct 2023

Cited by 1 | Viewed by 1814

Abstract

Breast cancer (BC) is the most common malignancy among women worldwide. In recent years, significant progress has been made in BC therapy. However, serious side effects resulting from the use of standard chemotherapeutic drugs, as well as the phenomenon of multidrug resistance (MDR), [...] Read more.

Breast cancer (BC) is the most common malignancy among women worldwide. In recent years, significant progress has been made in BC therapy. However, serious side effects resulting from the use of standard chemotherapeutic drugs, as well as the phenomenon of multidrug resistance (MDR), limit the effectiveness of approved therapies. Advanced research in the BC area is necessary to create more effective and safer forms of therapy to improve the outlook for individuals diagnosed with this aggressive neoplasm. For decades, plants and natural products with anticancer properties have been successfully utilized in treating various medical conditions. Anthraquinone derivatives are tricyclic secondary metabolites of natural origin that have been identified in plants, lichens, and fungi. They represent a few botanical families, e.g., Rhamnaceae, Rubiaceae, Fabaceae, Polygonaceae, and others. The review comprehensively covers and analyzes the most recent advances in the anticancer activity of 1,8-dihydroanthraquinone derivatives (emodin, aloe-emodin, hypericin, chrysophanol, rhein, and physcion) applied both individually, or in combination with other chemotherapeutic agents, in in vitro and in vivo BC models. The application of nanoparticles for in vitro and in vivo evidence in the context of 1,8-dihydroanthraquinone derivatives was also described. Full article

(This article belongs to the Special Issue Molecular Mechanisms and New Therapies for Breast Cancer)

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