International Journal of Molecular Sciences

Editorial

4 pages, 173 KiB

Open AccessEditorial

Special Issue: “Molecular Signatures of Gynecological Cancers—Breast Cancer, Ovarian Cancer, Cervical Cancer, and Endometrial Cancer 2.0”

by Lyudmila Gulyaeva

Int. J. Mol. Sci. 2024, 25(20), 11275; https://doi.org/10.3390/ijms252011275 - 20 Oct 2024

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Abstract

Cancer of women’s reproductive organs (gynecological cancers) and breast cancer affect women all over the world [...] Full article

(This article belongs to the Special Issue Molecular Signatures of Gynecological Cancers—Breast Cancer, Ovarian Cancer, Cervical Cancer, and Endometrial Cancer 2.0)

Research

Jump to: Editorial, Review

19 pages, 6339 KiB

Open AccessArticle

Autocrine Motility Factor and Its Peptide Derivative Inhibit Triple-Negative Breast Cancer by Regulating Wound Repair, Survival, and Drug Efflux

by Se Gie Kim, Seok Joong Kim, Thanh Van Duong, Yuhan Cho, Bogeun Park, Ulhas Sopanrao Kadam, Hee Sung Park and Jong Chan Hong

Int. J. Mol. Sci. 2024, 25(21), 11714; https://doi.org/10.3390/ijms252111714 - 31 Oct 2024

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Abstract

Triple-negative breast cancer (TNBC) presents a significant challenge in oncology due to its aggressive nature and limited targeted therapeutic options. This study explores the potential of autocrine motility factor (AMF) and an AMF-derived peptide as novel treatments for TNBC. AMF, primarily secreted by [...] Read more.

Triple-negative breast cancer (TNBC) presents a significant challenge in oncology due to its aggressive nature and limited targeted therapeutic options. This study explores the potential of autocrine motility factor (AMF) and an AMF-derived peptide as novel treatments for TNBC. AMF, primarily secreted by neoplastic cells, plays a crucial role in cancer cell motility, metastasis, and proliferation. The research demonstrates that AMF and its derived peptide inhibit TNBC cell proliferation by modulating cellular migration, redox homeostasis, apoptotic pathways, and drug efflux mechanisms. Dose-dependent antiproliferative effects were observed across three TNBC cell lines, with higher concentrations impairing cellular migration. Mechanistic studies revealed decreased glucose-6-phosphate dehydrogenase expression and elevated reactive oxygen species production, suggesting redox imbalance as a primary mediator of apoptosis. Combination studies with conventional therapeutics showed near-complete eradication of resistant TNBC cells. The observed reduction in p53 levels and increased intranuclear doxorubicin accumulation highlight the AMF/AMF peptide’s potential as multidrug resistance modulators. This study underscores the promise of using AMF/AMF peptide as a novel therapeutic approach for TNBC, addressing current treatment limitations and warranting further investigation. Full article

(This article belongs to the Special Issue Molecular Signatures of Gynecological Cancers—Breast Cancer, Ovarian Cancer, Cervical Cancer, and Endometrial Cancer 2.0)

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13 pages, 4265 KiB

Open AccessArticle

Predicting Response to Immunotargeted Therapy in Endometrial Cancer via Tumor Immune Microenvironment: A Multicenter, Observational Study

by Anastasia Maltseva, Anna Kalinchuk, Nataliya Chernorubashkina, Virab Sisakyan, Igor Lots, Alina Gofman, Yulia Anzhiganova, Elizaveta Martynova, Ruslan Zukov, Elena Aleksandrova, Larisa Kolomiets and Liubov Tashireva

Int. J. Mol. Sci. 2024, 25(7), 3933; https://doi.org/10.3390/ijms25073933 - 1 Apr 2024

Cited by 1 | Viewed by 1691

Abstract

Only one-third of patients with advanced MSS/pMMR endometrial cancer exhibit a lasting response to the combination treatment of Pembrolizumab and Lenvatinib. The combined administration of these two drugs is based on Lenvatinib’s ability to modulate the tumor microenvironment, enabling Pembrolizumab to exert its [...] Read more.

Only one-third of patients with advanced MSS/pMMR endometrial cancer exhibit a lasting response to the combination treatment of Pembrolizumab and Lenvatinib. The combined administration of these two drugs is based on Lenvatinib’s ability to modulate the tumor microenvironment, enabling Pembrolizumab to exert its effect. These findings underscore the importance of exploring tumor microenvironment parameters to identify markers that can accurately select candidates for this type of therapy. An open non-randomized observational association study was conducted at six clinical centers, involving a total of 28 patients with advanced MSS/pMMR endometrial cancer who received Pembrolizumab and Lenvatinib therapy. Using TSA-associated multiplex immunofluorescence, we analyzed the proportion of CD8+ T lymphocytes, CD20+ B lymphocytes, FoxP3+ T regulatory lymphocytes, and CD163+ macrophages in tumor samples prior to immunotargeted therapy. The percentage of CD20+ B lymphocytes and the CD8-to-CD20 lymphocytes ratio was significantly higher in patients who responded to treatment compared to non-responders (responders vs. non-responders: 0.24 (0.1–1.24)% vs. 0.08 (0.00–0.15)%, p = 0.0114; 1.44 (0.58–2.70) arb. unit vs. 19.00 (3.80–34.78) arb. unit, p = 0.0031). The sensitivity and specificity of these biomarkers were 85.71% and 70.59%, and 85.71% and 85.71%, respectively. The proportion of CD20+ B lymphocytes and the CD8-to-CD20 lymphocytes ratio in the stroma of endometrial cancer serves as both a prognostic marker of response to immunotargeted therapy and a prognostic factor for progression-free survival in patients. Full article

(This article belongs to the Special Issue Molecular Signatures of Gynecological Cancers—Breast Cancer, Ovarian Cancer, Cervical Cancer, and Endometrial Cancer 2.0)

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20 pages, 669 KiB

Open AccessArticle

Top–Down Proteomics of Human Saliva, Analyzed with Logistic Regression and Machine Learning Methods, Reveal Molecular Signatures of Ovarian Cancer

by Francesca Scebba, Stefano Salvadori, Silvia Cateni, Paola Mantellini, Francesca Carozzi, Simonetta Bisanzi, Cristina Sani, Marzia Robotti, Ivana Barravecchia, Francesca Martella, Valentina Colla and Debora Angeloni

Int. J. Mol. Sci. 2023, 24(21), 15716; https://doi.org/10.3390/ijms242115716 - 28 Oct 2023

Cited by 2 | Viewed by 1949

Abstract

Ovarian cancer (OC) is the most lethal of all gynecological cancers. Due to vague symptoms, OC is mostly detected at advanced stages, with a 5-year survival rate (SR) of only 30%; diagnosis at stage I increases the 5-year SR to 90%, suggesting that [...] Read more.

Ovarian cancer (OC) is the most lethal of all gynecological cancers. Due to vague symptoms, OC is mostly detected at advanced stages, with a 5-year survival rate (SR) of only 30%; diagnosis at stage I increases the 5-year SR to 90%, suggesting that early diagnosis is essential to cure OC. Currently, the clinical need for an early, reliable diagnostic test for OC screening remains unmet; indeed, screening is not even recommended for healthy women with no familial history of OC for fear of post-screening adverse events. Salivary diagnostics is considered a major resource for diagnostics of the future. In this work, we searched for OC biomarkers (BMs) by comparing saliva samples of patients with various stages of OC, breast cancer (BC) patients, and healthy subjects using an unbiased, high-throughput proteomics approach. We analyzed the results using both logistic regression (LR) and machine learning (ML) for pattern analysis and variable selection to highlight molecular signatures for OC and BC diagnosis and possibly re-classification. Here, we show that saliva is an informative test fluid for an unbiased proteomic search of candidate BMs for identifying OC patients. Although we were not able to fully exploit the potential of ML methods due to the small sample size of our study, LR and ML provided patterns of candidate BMs that are now available for further validation analysis in the relevant population and for biochemical identification. Full article

(This article belongs to the Special Issue Molecular Signatures of Gynecological Cancers—Breast Cancer, Ovarian Cancer, Cervical Cancer, and Endometrial Cancer 2.0)

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13 pages, 2099 KiB

Open AccessArticle

ASAP1 Expression in Invasive Breast Cancer and Its Prognostic Role

by Hosub Park, Hwangkyu Son, Hyebin Cha, Kihyuk Song, Seongsik Bang, Seungyun Jee, Hyunsung Kim, Jaekyung Myung, Su-Jin Shin, Chihwan Cha, Min Sung Chung and Seungsam Paik

Int. J. Mol. Sci. 2023, 24(18), 14355; https://doi.org/10.3390/ijms241814355 - 20 Sep 2023

Cited by 3 | Viewed by 1333

Abstract

Breast cancer is a major global health burden with high morbidity and mortality rates. Previous studies have reported that increased expression of ASAP1 is associated with poor prognosis in various types of cancer. This study was conducted on 452 breast cancer patients who [...] Read more.

Breast cancer is a major global health burden with high morbidity and mortality rates. Previous studies have reported that increased expression of ASAP1 is associated with poor prognosis in various types of cancer. This study was conducted on 452 breast cancer patients who underwent surgery at Hanyang University Hospital, Seoul, South Korea. Data on clinicopathological characteristics including molecular pathologic markers were collected. Immunohistochemical staining of ASAP1 expression level were used to classify patients into high and low groups. In total, 452 cases low ASAP1 expression group was associated with significantly worse recurrence-free survival (p = 0.029). In ER-positive cases (n = 280), the low ASAP1 expression group was associated with significantly worse overall survival (p = 0.039) and recurrence-free survival (p = 0.029). In multivariate cox analysis, low ASAP1 expression was an independent significant predictor of poor recurrence-free survival in the overall patient group (hazard ratio = 2.566, p = 0.002) and ER-positive cases (hazard ratio = 4.046, p = 0.002). In the analysis of the TCGA dataset, the low-expression group of ASAP1 protein demonstrated a significantly poorer progression-free survival (p = 0.005). This study reports that low ASAP1 expression was associated with worse recurrence-free survival in invasive breast cancer. Full article

(This article belongs to the Special Issue Molecular Signatures of Gynecological Cancers—Breast Cancer, Ovarian Cancer, Cervical Cancer, and Endometrial Cancer 2.0)

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16 pages, 7302 KiB

Open AccessArticle

SP1-Induced Upregulation of LncRNA AFAP1-AS1 Promotes Tumor Progression in Triple-Negative Breast Cancer by Regulating mTOR Pathway

by Fangyuan Li, Daheng Xian, Junying Huang, Longzhu Nie, Ting Xie, Qiang Sun, Xiaohui Zhang and Yidong Zhou

Int. J. Mol. Sci. 2023, 24(17), 13401; https://doi.org/10.3390/ijms241713401 - 29 Aug 2023

Cited by 3 | Viewed by 1839

Abstract

The long non-coding RNA (lncRNA) actin fiber-associated protein-1 antisense RNA 1 (AFAP1-AS1) exerted oncogenic activity in triple-negative breast cancer (TNBC). We designed this study and conducted it to investigate the upstream regulation mechanism of AFAP1-AS1 in TNBC tumorigenesis. In this work, we proved [...] Read more.

The long non-coding RNA (lncRNA) actin fiber-associated protein-1 antisense RNA 1 (AFAP1-AS1) exerted oncogenic activity in triple-negative breast cancer (TNBC). We designed this study and conducted it to investigate the upstream regulation mechanism of AFAP1-AS1 in TNBC tumorigenesis. In this work, we proved the localization of AFAP1-AS1 in the cytoplasm. We elucidated the mechanism by which the transcription factor specificity protein 1 (SP1) modulated AFAP1-AS1 in TNBC progression, which has yet to be thoroughly studied. Dual luciferase reporter assay and chromatin immunoprecipitation (ChIP) assay revealed a strong affinity of SP1 toward the promoter regions P3 of AFAP1-AS1, proving the gene expression regulation of AFAP1-AS1 via SP1 in TNBC. Additionally, SP1 could facilitate the tumorigenesis of TNBC cells in vitro and in vivo by regulating the AFAP1-AS1 expression. Furthermore, silenced AFAP1-AS1 suppressed the expression of genes in the mTOR pathway, such as eukaryotic translation initiation factor 4B (EIF4B), mitogen-activated protein kinase-associated protein 1 (MAPKAP1), SEH1-like nucleoporin (SEH1L), serum/glucocorticoid regulated kinase 1 (SGK1), and its target NEDD4-like E3 ubiquitin protein ligase (NEDD4L), and promoted the gene expression of s-phase kinase-associated protein 2 (SKP2). Overall, this study emphasized the oncogenic role of SP1 and AFAP1-AS1 in TNBC and illustrated the AFAP1-AS1 upstream interaction with SP1 and the downstream modulatory of mTOR signaling, thus offering insights into the tumorigenesis mechanism in TNBC. Full article

(This article belongs to the Special Issue Molecular Signatures of Gynecological Cancers—Breast Cancer, Ovarian Cancer, Cervical Cancer, and Endometrial Cancer 2.0)

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22 pages, 9421 KiB

Open AccessArticle

Loss of ANCO1 Expression Regulates Chromatin Accessibility and Drives Progression of Early-Stage Triple-Negative Breast Cancer

by Meng Yuan, Megan E. Barefoot, Kendell Peterson, Moray J. Campbell, Jan K. Blancato, Manjing Chen, Marcel O. Schmidt, Amber J. Kiliti, Hong-Bin Fang, Anton Wellstein, Anna T. Riegel and Ghada M. Sharif

Int. J. Mol. Sci. 2023, 24(14), 11505; https://doi.org/10.3390/ijms241411505 - 15 Jul 2023

Cited by 2 | Viewed by 1941

Abstract

Mutations in the gene ankyrin repeat domain containing 11 (ANKRD11/ANCO1) play a role in neurodegenerative disorders, and its loss of heterozygosity and low expression are seen in some cancers. Here, we show that low ANCO1 mRNA and protein expression [...] Read more.

Mutations in the gene ankyrin repeat domain containing 11 (ANKRD11/ANCO1) play a role in neurodegenerative disorders, and its loss of heterozygosity and low expression are seen in some cancers. Here, we show that low ANCO1 mRNA and protein expression levels are prognostic markers for poor clinical outcomes in breast cancer and that loss of nuclear ANCO1 protein expression predicts lower overall survival of patients with triple-negative breast cancer (TNBC). Knockdown of ANCO1 in early-stage TNBC cells led to aneuploidy, cellular senescence, and enhanced invasion in a 3D matrix. The presence of a subpopulation of ANCO1-depleted cells enabled invasion of the overall cell population in vitro and they converted more rapidly to invasive lesions in a xenograft mouse model. In ANCO1-depleted cells, ChIP-seq analysis showed a global increase in H3K27Ac signals that were enriched for AP-1, TEAD, STAT3, and NFκB motifs. ANCO1-regulated H3K27Ac peaks had a significantly higher overlap with known breast cancer enhancers compared to ANCO1-independent ones. H3K27Ac engagement was associated with transcriptional activation of genes in the PI3K-AKT, epithelial–mesenchymal transition (EMT), and senescence pathways. In conclusion, ANCO1 has hallmarks of a tumor suppressor whose loss of expression activates breast-cancer-specific enhancers and oncogenic pathways that can accelerate the early-stage progression of breast cancer. Full article

(This article belongs to the Special Issue Molecular Signatures of Gynecological Cancers—Breast Cancer, Ovarian Cancer, Cervical Cancer, and Endometrial Cancer 2.0)

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17 pages, 7923 KiB

Open AccessArticle

Pentoxifylline Inhibits TNF-α/TGF-β1-Induced Epithelial-Mesenchymal Transition via Suppressing the NF-κB Pathway and SERPINE1 Expression in CaSki Cells

by Luis Arturo Palafox-Mariscal, Pablo Cesar Ortiz-Lazareno, Luis Felipe Jave-Suárez, Adriana Aguilar-Lemarroy, María Martha Villaseñor-García, José Roberto Cruz-Lozano, Karen Lilith González-Martínez, Aníbal Samael Méndez-Clemente, Alejandro Bravo-Cuellar and Georgina Hernández-Flores

Int. J. Mol. Sci. 2023, 24(13), 10592; https://doi.org/10.3390/ijms241310592 - 24 Jun 2023

Cited by 6 | Viewed by 2314

Abstract

Cervical cancer (CC) is one of the most common and deadly types of female cancer worldwide. Late diagnosis in CC increases the risk of tumor cells spreading to distant organs (metastasis). The epithelial-mesenchymal transition (EMT) is a fundamental process of cancer metastasis. Inflammation [...] Read more.

Cervical cancer (CC) is one of the most common and deadly types of female cancer worldwide. Late diagnosis in CC increases the risk of tumor cells spreading to distant organs (metastasis). The epithelial-mesenchymal transition (EMT) is a fundamental process of cancer metastasis. Inflammation can lead to tumor progression, EMT induction, and metastasis. The inflammatory microenvironment is a potent inducer of EMT; inflammatory cytokines such as Tumor Necrosis Factor-alpha (TNF-α) and Transforming growth factor-beta (TGF-β1) activate transcriptional factors such as STAT3, Snail, Smad, and the Nuclear Factor kappa light-chain-enhancer of activated beta cells (NF-κΒ), which drive EMT. Anti-inflammatory compounds may be an option in the disruption of EMT. PenToXifylline (PTX) possesses potent anti-inflammatory effects by inhibiting NF-κB activity. In addition, PTX exerts an anti-fibrotic effect by decreasing Smad2/3/4. We hypothesize that PTX could exert anti-EMT effects. CaSki human cervical tumor cells were exposed to TNF-α 10 ng/mL and TGF-β1 alone or in combination for 5 days. Our results revealed that TNF-α and TGF-β1 induced N-cadherin and Vimentin, confirming the induction of EMT. Furthermore, the combination of cytokines synergized the expression of mesenchymal proteins, enhanced IκBα and p65 phosphorylation, and upregulated Serpin family E member 1 (SERPINE1) mRNA. PTX pretreatment prior to the addition of TNF-α and TGF-β1 significantly reduced N-cadherin and Vimentin levels. To our knowledge, this is the first time that this effect of PTX has been reported. Additionally, PTX reduced the phosphorylation of IκB-α and p65 and significantly decreased SERPINE1 expression, cell proliferation, migration, and invasion. In conclusion, PTX may counteract EMT in cervical cancer cells by decreasing the NF-κB and SERPINE1. Full article

(This article belongs to the Special Issue Molecular Signatures of Gynecological Cancers—Breast Cancer, Ovarian Cancer, Cervical Cancer, and Endometrial Cancer 2.0)

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11 pages, 915 KiB

Open AccessArticle

HRD Testing of Ovarian Cancer in Routine Practice: What Are We Dealing With?

by Tatiana Kekeeva, Yulia Andreeva, Alexander Tanas, Alexey Kalinkin, Svetlana Khokhlova, Tatiana Tikhomirova, Alexandra Tyulyandina, Anatoly Popov, Maria Kuzmenko, Mikhail Volkonsky, Natalia Chernorubashkina, Valeria Saevets, Vadim Dmitriev, Valentina Nechushkina, Olga Vedrova, Sergei Andreev, Sergey Kutsev and Vladimir Strelnikov

Int. J. Mol. Sci. 2023, 24(13), 10497; https://doi.org/10.3390/ijms241310497 - 22 Jun 2023

Cited by 4 | Viewed by 3681

Abstract

Assessment of homologous recombination deficiency (HRD) status is now essential for ovarian cancer patient management. The aim of our study was to analyze the influence of ethnic variations, tumor purity, and neoadjuvant chemotherapy (CT) on the determination of HRD scores as well as [...] Read more.

Assessment of homologous recombination deficiency (HRD) status is now essential for ovarian cancer patient management. The aim of our study was to analyze the influence of ethnic variations, tumor purity, and neoadjuvant chemotherapy (CT) on the determination of HRD scores as well as to evaluate feasibility of HRD testing with the Amoy HRD Focus Assay in routine clinical practice. The HRD status, including the BRCA status and genomic scar score (GSS), was analyzed in 452 ovarian cancer specimens. The successful rate of HRD testing was 86% (388/452). The BRCA mutational rate was 29% (114/388); 252 samples (65%) were classified as HRD-positive. Our data demonstrate the feasibility of internal HRD testing by the AmoyDx HRD Focus Panel for high-grade serous ovarian cancer (HGSOC), showing results similar to other methods. The HRD rate in the Russian population is very similar to those of other European populations, as is the BRCA mutation frequency. The most substantial contribution to HRD level diversity is testing criteria depending on intrahospital arrangements. The analysis shows that biallelic BRCA alterations had higher GSS compared with those with monoallelic inactivation, consistent with positive HRD status. The study indicates that grades 1–2 of the pathological response caused by chemotherapy affect HRD scores and suggests controlling for tumor purity of 40% or more as a critical factor for GSS measurement. Full article

(This article belongs to the Special Issue Molecular Signatures of Gynecological Cancers—Breast Cancer, Ovarian Cancer, Cervical Cancer, and Endometrial Cancer 2.0)

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14 pages, 3171 KiB

Open AccessArticle

Comparative Analysis of Tumor-Associated microRNAs and Tetraspanines from Exosomes of Plasma and Ascitic Fluids of Ovarian Cancer Patients

by Natalia Yunusova, Ekaterina Dzhugashvili, Alena Yalovaya, Larisa Kolomiets, Aleksei Shefer, Alina Grigor’eva, Alexey Tupikin, Irina Kondakova and Svetlana Tamkovich

Int. J. Mol. Sci. 2023, 24(1), 464; https://doi.org/10.3390/ijms24010464 - 27 Dec 2022

Cited by 9 | Viewed by 2101

Abstract

Ovarian cancer (OC) is one of the most common and fatal types of gynecological cancer. In the early phase of OC detection, the current treatment and diagnostic methods are not efficient and sensitive enough. Therefore, it is crucial to explore the mechanisms of [...] Read more.

Ovarian cancer (OC) is one of the most common and fatal types of gynecological cancer. In the early phase of OC detection, the current treatment and diagnostic methods are not efficient and sensitive enough. Therefore, it is crucial to explore the mechanisms of OC metastasis and discover valuable factors for early diagnosis of female cancers and novel therapeutic strategies for metastasis. Exosomes are known to be involved in the development, migration, and invasion of cancer cells, and their cargo could be useful for the non-invasive biopsy development. CD151- and Tspan8-positive exosomes are known to support the degradation of the extracellular matrix, and are involved in stroma remodeling, angiogenesis and cell motility, as well as the association of miR-24 and miR-101 with these processes. The objective of this study was to explore the relationship of these components of exosomal cargo, in patients with OC, to clarify the clinical significance of these markers in liquid biopsies. The levels of tetraspanins Tspan8+ and CD151+ exosomes were significantly higher in plasma exosomes of OC patients compared with healthy females (HFs). The relative levels of miR-24 and miR-101 in plasma exosomes of HFs were significantly higher than in plasma exosomes of OC patients, while the levels of these microRNAs in exosomes from plasma and ascites of ill females showed no difference. Our study revealed a strong direct correlation between the change in the ascites exosomes CD151+Tspan8+ subpopulation level and the expression levels of the ascites (R = 0.81, p < 0.05) and plasma exosomal miR-24 (R = 0.74, p < 0.05) in OC patients, which confirms the assumption that exosomal cargo act synergistically to increase cellular motility, affecting cellular processes and signaling. Bioinformatics analysis confirmed the involvement of CD151 and Tspan8 tetraspanins and genes controlled by miR-24-3p and miR-101 in signaling pathways, which are crucial for carcinogenesis, demonstrating that these tetraspanins and microRNAs are potential biomarkers for OC screening, and predictors of poor clinicopathological behavior in tumors. Full article

(This article belongs to the Special Issue Molecular Signatures of Gynecological Cancers—Breast Cancer, Ovarian Cancer, Cervical Cancer, and Endometrial Cancer 2.0)

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10 pages, 558 KiB

Open AccessArticle

Lynch Syndrome Identification in Saudi Cohort of Endometrial Cancer Patients Screened by Universal Approach

by Rong Bu, Abdul K. Siraj, Sandeep Kumar Parvathareddy, Kaleem Iqbal, Saud Azam, Zeeshan Qadri, Maha Al-Rasheed, Wael Haqawi, Mark Diaz, Khadija Alobaisi, Padmanaban Annaiyappanaidu, Nabil Siraj, Hamed AlHusaini, Osama Alomar, Ismail A. Al-Badawi, Fouad Al-Dayel and Khawla S. Al-Kuraya

Int. J. Mol. Sci. 2022, 23(20), 12299; https://doi.org/10.3390/ijms232012299 - 14 Oct 2022

Cited by 1 | Viewed by 2229

Abstract

Lynch syndrome (LS) is the most common cause of inherited endometrial cancer (EC). The prevalence and molecular characteristic of LS in Middle Eastern women with EC have been underexplored. To evaluate the frequency of LS in a cohort of EC patients from Saudi [...] Read more.

Lynch syndrome (LS) is the most common cause of inherited endometrial cancer (EC). The prevalence and molecular characteristic of LS in Middle Eastern women with EC have been underexplored. To evaluate the frequency of LS in a cohort of EC patients from Saudi Arabia, a total of 436 EC cases were screened utilizing immunohistochemistry (IHC), MLH1 promoter methylation analysis and next-generation sequencing technology. A total of 53 of 436 (12.2%) ECs were classified as DNA mismatch repair-deficient (dMMR). MLH1 promoter hypermethylation was detected in 30 ECs (6.9%). Three ECs (0.7%) were found to be LS harboring germline pathogenic variants (PVs)/likely pathogenic variants (LPVs): two in the MSH2 gene and one in the MSH6 gene. Three ECs (0.7%) were Lynch-like syndrome (LLS) carrying double somatic MSH2 PVs/LPVs. Seven cases were found to have variants of uncertain significance in cancer-related genes other than MMR genes. Our results indicate that LS prevalence is low among Saudi EC patients and LLS is as common as LS in this ethnicity. Our findings could help in better understanding of the prevalence and mutational spectrum of this syndrome in Saudi Arabia, which may help in defining best strategies for LS identification, prevention and genetic counseling for EC patients. Full article

(This article belongs to the Special Issue Molecular Signatures of Gynecological Cancers—Breast Cancer, Ovarian Cancer, Cervical Cancer, and Endometrial Cancer 2.0)

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Review

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23 pages, 1732 KiB

Open AccessReview

Tissue Inhibitor of Metalloproteinase 3: Unravelling Its Biological Function and Significance in Oncology

by Wei-Ting Lee, Pei-Ying Wu, Ya-Min Cheng and Yu-Fang Huang

Int. J. Mol. Sci. 2024, 25(6), 3191; https://doi.org/10.3390/ijms25063191 - 10 Mar 2024

Cited by 4 | Viewed by 2694

Abstract

Tissue inhibitor of metalloproteinases-3 (TIMP3) is vital in regulating several biological processes. TIMP3 exerts antitumour effects via matrix metalloproteinase (MMP)-dependent and MMP-independent pathways. Due to promoter methylation and miRNA binding, TIMP3 expression has been observed to decrease in various cancers. Consequently, the migration [...] Read more.

Tissue inhibitor of metalloproteinases-3 (TIMP3) is vital in regulating several biological processes. TIMP3 exerts antitumour effects via matrix metalloproteinase (MMP)-dependent and MMP-independent pathways. Due to promoter methylation and miRNA binding, TIMP3 expression has been observed to decrease in various cancers. Consequently, the migration and invasion of cancer cells increases. Conflicting results have reported that expression levels of TIMP3 in primary and advanced cancers are higher than those in healthy tissues. Therefore, the role of TIMP3 in cancer biology and progression needs to be elucidated. This review provides an overview of TIMP3, from its biological function to its effects on various cancers. Moreover, gynaecological cancers are discussed in detail. TIMP3 has been associated with cervical adenocarcinoma as well as cancer development in serous ovarian cancer and breast cancer metastasis. However, the relationship between TIMP3 and endometrial cancers remains unclear. TIMP3 may be a useful biomarker for gynaecological cancers and is a potential target for future cancer therapy. Full article

(This article belongs to the Special Issue Molecular Signatures of Gynecological Cancers—Breast Cancer, Ovarian Cancer, Cervical Cancer, and Endometrial Cancer 2.0)

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34 pages, 2355 KiB

Open AccessReview

Unveiling the Immune Microenvironment’s Role in Breast Cancer: A Glimpse into Promising Frontiers

by Amalia Kotsifaki, Nektarios Alevizopoulos, Vassiliki Dimopoulou and Athanasios Armakolas

Int. J. Mol. Sci. 2023, 24(20), 15332; https://doi.org/10.3390/ijms242015332 - 18 Oct 2023

Cited by 16 | Viewed by 2470

Abstract

Breast cancer (BC), one of the most widespread and devastating diseases affecting women worldwide, presents a significant public health challenge. This review explores the emerging frontiers of research focused on deciphering the intricate interplay between BC cells and the immune microenvironment. Understanding the [...] Read more.

Breast cancer (BC), one of the most widespread and devastating diseases affecting women worldwide, presents a significant public health challenge. This review explores the emerging frontiers of research focused on deciphering the intricate interplay between BC cells and the immune microenvironment. Understanding the role of the immune system in BC is critical as it holds promise for novel therapeutic approaches and precision medicine strategies. This review delves into the current literature regarding the immune microenvironment’s contribution to BC initiation, progression, and metastasis. It examines the complex mechanisms by which BC cells interact with various immune cell populations, including tumor-infiltrating lymphocytes (TILs) and tumor-associated macrophages (TAMs). Furthermore, this review highlights the impact of immune-related factors, such as cytokines and immune checkpoint molecules. Additionally, this comprehensive analysis sheds light on the potential biomarkers associated with the immune response in BC, enabling early diagnosis and prognostic assessment. The therapeutic implications of targeting the immune microenvironment are also explored, encompassing immunotherapeutic strategies and combination therapies to enhance treatment efficacy. The significance of this review lies in its potential to pave the way for novel therapeutic interventions, providing clinicians and researchers with essential knowledge to design targeted and personalized treatment regimens for BC patients. Full article

(This article belongs to the Special Issue Molecular Signatures of Gynecological Cancers—Breast Cancer, Ovarian Cancer, Cervical Cancer, and Endometrial Cancer 2.0)

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