Editorial

9 pages, 236 KiB

Open AccessEditorial

Recent Advances in Breast Cancer Research

by Daniela Grimm

Int. J. Mol. Sci. 2023, 24(15), 11990; https://doi.org/10.3390/ijms241511990 - 26 Jul 2023

Viewed by 917

This Special Issue (SI), titled “Recent Advances in Breast Cancer Research”, covers 12 research articles and 1 communication in the field of breast cancer (BC) research [...] Full article

(This article belongs to the Special Issue Recent Advances in Breast Cancer Research)

Research

Jump to: Editorial

11 pages, 2329 KiB

Open AccessCommunication

Gene Expression Profiling of Fibroepithelial Lesions of the Breast

by Xiaomo Li, Eric Vail, Horacio Maluf, Manita Chaum, Matthew Leong, Joseph Lownik, Mingtian Che, Armando Giuliano, Duoyao Cao and Farnaz Dadmanesh

Int. J. Mol. Sci. 2023, 24(10), 9041; https://doi.org/10.3390/ijms24109041 - 20 May 2023

Cited by 4 | Viewed by 1603

Abstract

Fibroepithelial lesions of the breast (FELs) are a heterogeneous group of neoplasms exhibiting a histologic spectrum ranging from fibroadenomas (FAs) to malignant phyllodes tumors (PTs). Despite published histologic criteria for their classification, it is common for such lesions to exhibit overlapping features, leading [...] Read more.

Fibroepithelial lesions of the breast (FELs) are a heterogeneous group of neoplasms exhibiting a histologic spectrum ranging from fibroadenomas (FAs) to malignant phyllodes tumors (PTs). Despite published histologic criteria for their classification, it is common for such lesions to exhibit overlapping features, leading to subjective interpretation and interobserver disagreements in histologic diagnosis. Therefore, there is a need for a more objective diagnostic modality to aid in the accurate classification of these lesions and to guide appropriate clinical management. In this study, the expression of 750 tumor-related genes was measured in a cohort of 34 FELs (5 FAs, 9 cellular FAs, 9 benign PTs, 7 borderline PTs, and 4 malignant PTs). Differentially expressed gene analysis, gene set analysis, pathway analysis, and cell type analysis were performed. Genes involved in matrix remodeling and metastasis (e.g., MMP9, SPP1, COL11A1), angiogenesis (VEGFA, ITGAV, NFIL3, FDFR1, CCND2), hypoxia (ENO1, HK1, CYBB, HK2), metabolic stress (e.g., UBE2C, CDKN2A, FBP1), cell proliferation (e.g., CENPF, CCNB1), and the PI3K-Akt pathway (e.g., ITGB3, NRAS) were highly expressed in malignant PTs and less expressed in borderline PTs, benign PTs, cellular FAs, and FAs. The overall gene expression profiles of benign PTs, cellular FAs, and FAs were very similar. Although a slight difference was observed between borderline and benign PTs, a higher degree of difference was observed between borderline and malignant PTs. Additionally, the macrophage cell abundance scores and CCL5 were significantly higher in malignant PTs compared with all other groups. Our results suggest that the gene-expression-profiling-based approach could lead to further stratification of FELs and may provide clinically useful biological and pathophysiological information to improve the existing histologic diagnostic algorithm. Full article

(This article belongs to the Special Issue Recent Advances in Breast Cancer Research)

► Show Figures

Figure 1

26 pages, 2779 KiB

Open AccessArticle

CCL2-Mediated Stromal Interactions Drive Macrophage Polarization to Increase Breast Tumorigenesis

by Maddison Archer, Sarah M. Bernhardt, Leigh J. Hodson, Lucy Woolford, Mark Van der Hoek, Pallave Dasari, Andreas Evdokiou and Wendy V. Ingman

Int. J. Mol. Sci. 2023, 24(8), 7385; https://doi.org/10.3390/ijms24087385 - 17 Apr 2023

Cited by 2 | Viewed by 1590

Abstract

CCL2 is an inflammatory cytokine that regulates macrophage activity and is implicated in increased mammographic density and early breast tumorigenesis. The role of CCL2 in mediating stromal interactions that contribute to breast tumorigenesis has yet to be fully elucidated. THP-1-derived macrophages and mammary [...] Read more.

CCL2 is an inflammatory cytokine that regulates macrophage activity and is implicated in increased mammographic density and early breast tumorigenesis. The role of CCL2 in mediating stromal interactions that contribute to breast tumorigenesis has yet to be fully elucidated. THP-1-derived macrophages and mammary fibroblasts were co-cultured for 72 h. Fibroblasts and macrophages were analysed for phenotype, expression of inflammatory and ECM-regulatory genes and collagen production. Mice overexpressing CCL2 in the mammary glands were analysed for global gene expression by RNAseq at 12 weeks of age. These mice were cross-bred with PyMT mammary tumour mice to examine the role of CCL2 in tumorigenesis. The co-culture of macrophages with fibroblasts resulted in macrophage polarization towards an M2 phenotype, and upregulated expression of CCL2 and other genes associated with inflammation and ECM remodelling. CCL2 increased the production of insoluble collagen by fibroblasts. A global gene expression analysis of CCL2 overexpressing mice revealed that CCL2 upregulates cancer-associated gene pathways and downregulates fatty acid metabolism gene pathways. In the PyMT mammary tumour model, CCL2 overexpressing mice exhibited increased macrophage infiltration and early tumorigenesis. Interactions between macrophages and fibroblasts regulated by CCL2 can promote an environment that may increase breast cancer risk, leading to enhanced early tumorigenesis. Full article

(This article belongs to the Special Issue Recent Advances in Breast Cancer Research)

► Show Figures

Figure 1

30 pages, 3674 KiB

Open AccessArticle

Young Shoots of Red Beet and the Root at Full Maturity Inhibit Proliferation and Induce Apoptosis in Breast Cancer Cell Lines

by Ewelina Piasna-Słupecka, Teresa Leszczyńska, Mariola Drozdowska, Kinga Dziadek, Barbara Domagała, Dominik Domagała and Aneta Koronowicz

Int. J. Mol. Sci. 2023, 24(8), 6889; https://doi.org/10.3390/ijms24086889 - 07 Apr 2023

Cited by 1 | Viewed by 2215

Abstract

Modern medicine is struggling with the problem of fully effective treatment of neoplastic diseases despite deploying innovative chemotherapeutic agents. Therefore, undertaking cancer-prevention measures, such as proper eating habits, should be strongly recommended. The present research aimed to compare the effects of juice from [...] Read more.

Modern medicine is struggling with the problem of fully effective treatment of neoplastic diseases despite deploying innovative chemotherapeutic agents. Therefore, undertaking cancer-prevention measures, such as proper eating habits, should be strongly recommended. The present research aimed to compare the effects of juice from young shoots of beetroot compared to juice from root at full maturity on human breast cancer and normal cells. The juice from young shoots, both in the native and digested form, was most often a significantly stronger inhibitor of the proliferation of both analyzed breast cancer cell lines (MCF-7 and MDA-MB-231), compared to the native and digested juice from red beetroot. Regardless of juice type, a significantly greater reduction was most often shown in the proliferation of estrogen-dependent cells (MCF-7 line) than of estrogen-independent cells (MDA-MB-231 line). All analyzed types of beetroot juice and, in particular, the ones from young shoots and the root subjected to digestion and absorption, exerted an antiproliferative and apoptotic effect (pinpointing the internal apoptosis pathway) on the cells of both cancer lines studied. There is a need to continue the research to comprehensively investigate the factors responsible for both these effects. Full article

(This article belongs to the Special Issue Recent Advances in Breast Cancer Research)

► Show Figures

Figure 1

17 pages, 5763 KiB

Open AccessArticle

NUF2 Promotes Breast Cancer Development as a New Tumor Stem Cell Indicator

by Yang Deng, Jiapeng Li, Yingjie Zhang, Hao Hu, Fujian Wan, Hang Min, Hao Zhou, Lixing Gu, Xinghua Liao, Jingjiao Zhou and Jun Zhou

Int. J. Mol. Sci. 2023, 24(4), 4226; https://doi.org/10.3390/ijms24044226 - 20 Feb 2023

Cited by 3 | Viewed by 1774

Abstract

Multiple new subtypes of breast cancer (BRCA) are identified in women each year, rendering BRCA the most common and rapidly expanding form of cancer in females globally. NUF2 has been identified as a prognostic factor in various human cancers, regulating cell apoptosis and [...] Read more.

Multiple new subtypes of breast cancer (BRCA) are identified in women each year, rendering BRCA the most common and rapidly expanding form of cancer in females globally. NUF2 has been identified as a prognostic factor in various human cancers, regulating cell apoptosis and proliferation. However, its role in BRCA prognosis has not been clarified. This study explored the role of NUF2 in breast cancer development and prognosis using informatic analysis combined with in vivo intracellular studies. Through the online website TIMER, we evaluated the transcription profile of NUF2 across a variety of different cancer types and found that NUF2 mRNA was highly expressed in BRCA patients. Its transcription level was found to be related to the subtype, pathological stage, and prognosis of BRCA. The R program analysis showed a correlation of NUF2 with cell proliferation and tumor stemness in the BRCA patient samples. Subsequently, the association between the NUF2 expression level and immune cell infiltration was analyzed using the XIANTAO and TIMER tools. The results revealed that NUF2 expression was correlated with the responses of multiple immune cells. Furthermore, we observed the effect of NUF2 expression on tumor stemness in BRCA cell lines in vivo. The experimental results illuminated that the overexpression of NUF2 statistically upregulated the proliferation and tumor stemness ability of the BRCA cell lines MCF-7 and Hs-578T. Meanwhile, the knockdown of NUF2 inhibited the abilities of both cell lines, a finding which was verified by analyzing the subcutaneous tumorigenic ability in nude mice. In summary, this study suggests that NUF2 may play a key role in the development and progression of BRCA by affecting tumor stemness. As a stemness indicator, it has the potential to be one of the markers for the diagnosis of BRCA. Full article

(This article belongs to the Special Issue Recent Advances in Breast Cancer Research)

► Show Figures

Figure 1

24 pages, 3170 KiB

Open AccessArticle

ERβ1 Sensitizes and ERβ2 Desensitizes ERα-Positive Breast Cancer Cells to the Inhibitory Effects of Tamoxifen, Fulvestrant and Their Combination with All-Trans Retinoic Acid

by Aggeliki K. Meligova, Dimitra Siakouli, Sotiria Stasinopoulou, Despoina S. Xenopoulou, Maria Zoumpouli, Vassiliki Ganou, Eleni-Fani Gkotsi, Aristotelis Chatziioannou, Olga Papadodima, Eleftherios Pilalis, Michael N. Alexis and Dimitra J. Mitsiou

Int. J. Mol. Sci. 2023, 24(4), 3747; https://doi.org/10.3390/ijms24043747 - 13 Feb 2023

Cited by 2 | Viewed by 1872

Abstract

Adjuvant endocrine therapy (AET) is the treatment of choice for early-stage estrogen receptor alpha (ERα)-positive breast cancer (BC). However, almost 40% of tamoxifen-treated cases display no response or a partial response to AET, thus increasing the need for new treatment options and strong [...] Read more.

Adjuvant endocrine therapy (AET) is the treatment of choice for early-stage estrogen receptor alpha (ERα)-positive breast cancer (BC). However, almost 40% of tamoxifen-treated cases display no response or a partial response to AET, thus increasing the need for new treatment options and strong predictors of the therapeutic response of patients at high risk of relapse. In addition to ERα, BC research has focused on ERβ1 and ERβ2 (isoforms of ERβ), the second ER isotype. At present, the impact of ERβ isoforms on ERα-positive BC prognosis and treatment remains elusive. In the present study, we established clones of MCF7 cells constitutively expressing human ERβ1 or ERβ2 and investigated their role in the response of MCF7 cells to antiestrogens [4-hydroxytamoxifen (OHΤ) and fulvestrant (ICI182,780)] and retinoids [all-trans retinoic acid (ATRA)]. We show that, compared to MCF7 cells, MCF7-ERβ1 and MCF7-ERβ2 cells were sensitized and desensitized, respectively, to the antiproliferative effect of the antiestrogens, ATRA and their combination and to the cytocidal effect of the combination of OHT and ATRA. Analysis of the global transcriptional changes upon OHT–ATRA combinatorial treatment revealed uniquely regulated genes associated with anticancer effects in MCF7-ERβ1 cells and cancer-promoting effects in MCF7-ERβ2 cells. Our data are favorable to ERβ1 being a marker of responsiveness and ERβ2 being a marker of resistance of MCF7 cells to antiestrogens alone and in combination with ATRA. Full article

(This article belongs to the Special Issue Recent Advances in Breast Cancer Research)

► Show Figures

Figure 1

17 pages, 3036 KiB

Open AccessArticle

GRHL2 Regulation of Growth/Motility Balance in Luminal versus Basal Breast Cancer

by Zi Wang, Bircan Coban, Chen-Yi Liao, Yao-Jun Chen, Qiuyu Liu and Erik H. J. Danen

Int. J. Mol. Sci. 2023, 24(3), 2512; https://doi.org/10.3390/ijms24032512 - 28 Jan 2023

Cited by 2 | Viewed by 1891

Abstract

The transcription factor Grainyhead-like 2 (GRHL2) is a critical transcription factor for epithelial tissues that has been reported to promote cancer growth in some and suppress aspects of cancer progression in other studies. We investigated its role in different breast cancer subtypes. In [...] Read more.

The transcription factor Grainyhead-like 2 (GRHL2) is a critical transcription factor for epithelial tissues that has been reported to promote cancer growth in some and suppress aspects of cancer progression in other studies. We investigated its role in different breast cancer subtypes. In breast cancer patients, GRHL2 expression was increased in all subtypes and inversely correlated with overall survival in basal-like breast cancer patients. In a large cell line panel, GRHL2 was expressed in luminal and basal A cells, but low or absent in basal B cells. The intersection of ChIP-Seq analysis in 3 luminal and 3 basal A cell lines identified conserved GRHL2 binding sites for both subtypes. A pathway analysis of ChIP-seq data revealed cell-cell junction regulation and epithelial migration as well as epithelial proliferation, as candidate GRHL2-regulated processes and further analysis of hub genes in these pathways showed similar regulatory networks in both subtypes. However, GRHL2 deletion in a luminal cell line caused cell cycle arrest while this was less prominent in a basal A cell line. Conversely, GRHL2 loss triggered enhanced migration in the basal A cells but failed to do so in the luminal cell line. ChIP-Seq and ChIP-qPCR demonstrated GRHL2 binding to CLDN4 and OVOL2 in both subtypes but not to other GRHL2 targets controlling cell-cell adhesion that were previously identified in other cell types, including CDH1 and ZEB1. Nevertheless, E-cadherin protein expression was decreased upon GRHL2 deletion especially in the luminal line and, in agreement with its selectively enhanced migration, only the basal A cell line showed concomitant induction of vimentin and N-cadherin. To address how the balance between growth reduction and aspects of EMT upon loss of GRHL2 affected in vivo behavior, we used a mouse basal A orthotopic transplantation model in which the GRHL2 gene was silenced. This resulted in reduced primary tumor growth and a reduction in number and size of lung colonies, indicating that growth suppression was the predominant consequence of GRHL2 loss. Altogether, these findings point to largely common but also distinct roles for GRHL2 in luminal and basal breast cancers with respect to growth and motility and indicate that, in agreement with its negative association with patient survival, growth suppression is the dominant response to GRHL2 loss. Full article

(This article belongs to the Special Issue Recent Advances in Breast Cancer Research)

► Show Figures

Figure 1

13 pages, 3789 KiB

Open AccessArticle

Expression of CD22 in Triple-Negative Breast Cancer: A Novel Prognostic Biomarker and Potential Target for CAR Therapy

by Tahir Zaib, Ke Cheng, Tingdang Liu, Ruyi Mei, Qin Liu, Xiaoling Zhou, Lifang He, Hibba Rashid, Qingdong Xie, Hanif Khan, Yien Xu, Pingnan Sun and Jundong Wu

Int. J. Mol. Sci. 2023, 24(3), 2152; https://doi.org/10.3390/ijms24032152 - 21 Jan 2023

Cited by 5 | Viewed by 2735

Abstract

Triple-negative breast cancer (TNBC) accounts for 15–20% of all breast cancer cases. Due to the lack of expression of well-known molecular targets [estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2)], there is a need for more alternative [...] Read more.

Triple-negative breast cancer (TNBC) accounts for 15–20% of all breast cancer cases. Due to the lack of expression of well-known molecular targets [estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2)], there is a need for more alternative treatment approaches in TNBC. Chimeric antigen receptor (CAR)-T cell-based immunotherapy treatment is one of the latest treatment technologies with outstanding therapeutic advances in the past decade, especially in the treatment of hematologic malignancies, but the therapeutic effects of CAR-T cells against solid tumors have not yet shown significant clinical benefits. Identification of highly specific CAR-T targets in solid tumors is also crucial for its successful treatment. CD22 is reported to be a multifunctional receptor that is mainly expressed on the surface of mature B-cells (lymphocytes) and is also highly expressed in most B-cell malignancies. This study aimed to investigate the expression of CD22 in TNBC. Bioinformatic analysis was performed to evaluate the expression of CD22 in breast carcinoma and normal tissues. RNA-seq data of normal and breast carcinoma patients were downloaded from The Cancer Genome Atlas (TCGA), and differential gene expression was performed using R language. Additionally, online bioinformatics web tools (GEPIA and TNM plot) were used to evaluate the expression of CD22 in breast carcinoma and normal tissues. Western blot (WB) analysis and immunofluorescence (IF) were performed to characterize the expression of CD22 in TNBC cell lines. Immunohistochemical (IHC) staining was performed on tumor specimens from 97 TNBC patients for CD22 expression. Moreover, statistical analysis was performed to analyze the association of clinical pathological parameters with CD22 expression. Correlation analysis between overall survival data of TNBC patients and CD22 expression was also performed. Differential gene expression analysis of TCGA data revealed that CD22 is among the upregulated differentially expressed genes (DEGs) with high expression in breast cancer, as compared to normal breast tissues. WB and IF analysis revealed high expression of CD22 in TNBC cell lines. IHC results also showed that approximately 62.89% (61/97) of TNBC specimens were stained positive for CD22. Cell membrane expression of CD22 was evident in 23.71% (23/97) of TNBC specimens, and 39.18% (38/97) of TNBC specimens showed cytoplasmic/membrane expression, while 37.11% (36/97) specimens were negative for CD22. Furthermore, significant associations were found between the size of tumors in TNBC patients and CD22 expression, which unveils its potential as a prognostic biomarker. No significant correlation was found between the overall survival of TNBC patients and CD22 expression. In conclusion, we demonstrated for the first time that CD22 is highly expressed in TNBC. Based on our findings, we anticipated that CD22 could be used as a prognostic biomarker in TNBC, and it might be a potential CAR-T target in TNBC for whom few therapeutic options exist. However, more large-scale studies and clinical trials will ensure its potential usefulness as a CAR-T target in TNBC. Full article

(This article belongs to the Special Issue Recent Advances in Breast Cancer Research)

► Show Figures

Figure 1

10 pages, 1037 KiB

Open AccessArticle

Discrimination between Complete versus Non-Complete Pathologic Response to Neoadjuvant Therapy Using Ultrasensitive Mutation Analysis: A Proof-of-Concept Study in BRCA1-Driven Breast Cancer Patients

by Anna P. Sokolenko, Fedor V. Moiseyenko, Aglaya G. Iyevleva, Alexandr O. Ivantsov, Georgiy D. Dolmatov, Ksenia V. Shelekhova, Elizaveta V. Gulo, Anastasya X. Topal, Elizaveta V. Artemieva, Nuriniso H. Abduloeva, Nikita A. Rysev, Daria A. Barsova, Natalia V. Levchenko, Nikita M. Volkov, Vitaliy V. Egorenkov, Vladimir M. Moiseyenko and Evgeny N. Imyanitov

Int. J. Mol. Sci. 2023, 24(3), 1870; https://doi.org/10.3390/ijms24031870 - 18 Jan 2023

Cited by 1 | Viewed by 1853

Abstract

Neoadjuvant chemotherapy (NACT) for breast cancer (BC) often results in pathologic complete response (pCR), i.e., the complete elimination of visible cancer cells. It is unclear whether the use of ultrasensitive genetic methods may still detect residual BC cells in complete responders. Breast carcinomas [...] Read more.

Neoadjuvant chemotherapy (NACT) for breast cancer (BC) often results in pathologic complete response (pCR), i.e., the complete elimination of visible cancer cells. It is unclear whether the use of ultrasensitive genetic methods may still detect residual BC cells in complete responders. Breast carcinomas arising in BRCA1 mutation carriers almost always carry alterations of the TP53 gene thus providing an opportunity to address this question. The analysis of consecutive BC patients treated by NACT revealed a higher pCR rate in BRCA1-driven vs. BRCA1-wildtype BCs (13/24 (54%) vs. 29/192 (15%), p < 0.0001). Twelve pre-/post-NACT tissue pairs obtained from BRCA1 mutation carriers were available for the study. While TP53 mutation was identified in all chemonaive tumors, droplet digital PCR (ddPCR) analysis of the post-NACT tumor bed revealed the persistence of this alteration in all seven pCR-non-responders but in none of five pCR responders. Eleven patients provided to the study post-NACT tissue samples only; next-generation sequencing (NGS) analysis revealed mutated TP53 copies in all six cases without pCR but in none of five instances of pCR. In total, TP53 mutation was present in post-NACT tissues in all 13 cases without pCR, but in none of 10 patients with pCR (p < 0.000001). Therefore, the lack of visible tumor cells in the post-NACT tumor bed is indeed a reliable indicator of the complete elimination of transformed clones. Failure of ultrasensitive methods to identify patients with minimal residual disease among pCR responders suggests that the result of NACT is a categorical rather than continuous variable, where some patients are destined to be cured while others ultimately fail to experience tumor eradication. Full article

(This article belongs to the Special Issue Recent Advances in Breast Cancer Research)

► Show Figures

Figure 1

23 pages, 4884 KiB

Open AccessArticle

Long-Term Simulation of Microgravity Induces Changes in Gene Expression in Breast Cancer Cells

by Jayashree Sahana, José Luis Cortés-Sánchez, Viviann Sandt, Daniela Melnik, Thomas J. Corydon, Herbert Schulz, Zexi Cai, Katja Evert, Daniela Grimm and Markus Wehland

Int. J. Mol. Sci. 2023, 24(2), 1181; https://doi.org/10.3390/ijms24021181 - 07 Jan 2023

Cited by 7 | Viewed by 2552

Abstract

Microgravity changes the gene expression pattern in various cell types. This study focuses on the breast cancer cell lines MCF-7 (less invasive) and MDA-MB-231 (triple-negative, highly invasive). The cells were cultured for 14 days under simulated microgravity (s-µg) conditions using a [...] Read more.

Microgravity changes the gene expression pattern in various cell types. This study focuses on the breast cancer cell lines MCF-7 (less invasive) and MDA-MB-231 (triple-negative, highly invasive). The cells were cultured for 14 days under simulated microgravity (s-µg) conditions using a random positioning machine (RPM). We investigated cytoskeletal and extracellular matrix (ECM) factors as well as focal adhesion (FA) and the transmembrane proteins involved in different cellular signaling pathways (MAPK, PAM and VEGF). The mRNA expressions of 24 genes of interest (TUBB, ACTB, COL1A1, COL4A5, LAMA3, ITGB1, CD44, VEGF, FLK1, EGFR, SRC, FAK1, RAF1, AKT1, ERK1, MAPK14, MAP2K1, MTOR, RICTOR, VCL, PXN, CDKN1, CTNNA1 and CTNNB1) were determined by quantitative real-time PCR (qPCR) and studied using STRING interaction analysis. Histochemical staining was carried out to investigate the morphology of the adherent cells (ADs) and the multicellular spheroids (MCSs) after RPM exposure. To better understand this experimental model in the context of breast cancer patients, a weighted gene co-expression network analysis (WGCNA) was conducted to obtain the expression profiles of 35 breast cell lines from the HMS LINCS Database. The qPCR-verified genes were searched in the mammalian phenotype database and the human genome-wide association studies (GWAS) Catalog. The results demonstrated the positive association between the real metastatic microtumor environment and MCSs with respect to the extracellular matrix, cytoskeleton, morphology, different cellular signaling pathway key proteins and several other components. In summary, the microgravity-engineered three-dimensional MCS model can be utilized to study breast cancer cell behavior and to assess the therapeutic efficacies of drugs against breast cancer in the future. Full article

(This article belongs to the Special Issue Recent Advances in Breast Cancer Research)

► Show Figures

Figure 1

11 pages, 2349 KiB

Open AccessArticle

Tumor Microenvironment in Male Breast Carcinoma with Emphasis on Tumor Infiltrating Lymphocytes and PD-L1 Expression

by Iva Brcic, Andrea Maria Kluba, Theresa Marie Godschachner, Christoph Suppan, Peter Regitnig, Nadia Dandachi, Sigurd Friedwald Lax and Marija Balić

Int. J. Mol. Sci. 2023, 24(1), 818; https://doi.org/10.3390/ijms24010818 - 03 Jan 2023

Cited by 3 | Viewed by 2100

Abstract

Male breast cancer (MBC) is rare and usually presents as a locally advanced disease. Stromal tumor-infiltrating lymphocytes (sTILs) are associated with a better response to neoadjuvant chemotherapy and improved prognosis in all molecular subtypes of female breast cancer, but their role in MBC [...] Read more.

Male breast cancer (MBC) is rare and usually presents as a locally advanced disease. Stromal tumor-infiltrating lymphocytes (sTILs) are associated with a better response to neoadjuvant chemotherapy and improved prognosis in all molecular subtypes of female breast cancer, but their role in MBC is less clear. We studied sTILs and the expression of programmed cell death ligand 1 (PD-L1) and pan-TRK in MBC. We retrospectively studied 113 cases of MBC surgically treated between 1988 and 2015. The tumors were evaluated for histological type and grade, stage, intrinsic subtype and sTILs. We performed immunohistochemistry for PD-L1 (clone SP142) and pan-TRK (clone EPR17341) on tissue microarrays. Pan-TRK positive cases were further analyzed by next-generation sequencing. The median age was 69 years (range 60–77). Invasive carcinoma of no special type was found in 94.7% of cases, of which 53.1% were grade 2. Estrogen receptor was positive in 92% of the tumors, progesterone receptor in 85.8%, androgen receptor in 70.8%; 4.4% were human epidermal growth factor receptor 2 (HER2)-positive, and 55.8% HER2-low. 40.7% of tumors were luminal A and 51.3% luminal B, 4.4% HER2-enriched and 3.5% triple negative carcinoma. sTILs density was <50% in 96.4% of the tumors, >50% in 3.6% of the tumors. PD-L1 immune cell score >1% was found in 7.1% of the tumors (all of luminal subtype). A weak focal cytoplasmic pan-TRK staining was present in 8.8% but without NTRK fusion. Neither sTILs nor PD-L1 had statistically significant outcomes. Our findings suggest that a subset of MBC patients harbors an immunological environment characterized by increased sTILs with PD-L1 expression. These patients may potentially benefit from immune checkpoint inhibitor therapy. Frequent HER2-low may offer novel anti-HER2 treatment options. Full article

(This article belongs to the Special Issue Recent Advances in Breast Cancer Research)

► Show Figures

Figure 1

20 pages, 3529 KiB

Open AccessArticle

Prolonged Exposure to Simulated Microgravity Changes Release of Small Extracellular Vesicle in Breast Cancer Cells

by Petra M. Wise, Jayashree Sahana, Paolo Neviani, Thomas Juhl Corydon, Herbert Schulz, Markus Wehland, Manfred Infanger and Daniela Grimm

Int. J. Mol. Sci. 2022, 23(24), 16095; https://doi.org/10.3390/ijms232416095 - 17 Dec 2022

Cited by 4 | Viewed by 1803

Abstract

Breast cancer is the leading cause of cancer incidence worldwide and among the five leading causes of cancer mortality. Despite major improvements in early detection and new treatment approaches, the need for better outcomes and quality of life for patients is still high. [...] Read more.

Breast cancer is the leading cause of cancer incidence worldwide and among the five leading causes of cancer mortality. Despite major improvements in early detection and new treatment approaches, the need for better outcomes and quality of life for patients is still high. Extracellular vesicles play an important role in tumor biology, as they are able to transfer information between cells of different origins and locations. Their potential value as biomarkers or for targeted tumor therapy is apparent. In this study, we analyzed the supernatants of MCF-7 breast cancer cells, which were harvested following 5 or 10 days of simulated microgravity on a Random Positioning Machine (RPM). The primary results showed a substantial increase in released vesicles following incubation under simulated microgravity at both time points. The distribution of subpopulations regarding their surface protein expression is also altered; the minimal changes between the time points hint at an early adaption. This is the first step in gaining further insight into the mechanisms of tumor progression, metastasis, the education of the tumor microenvironments, and preparation of the metastatic niche. Additionally, this may lighten up the processes of the rapid cellular adaptions in the organisms of space travelers during spaceflights. Full article

(This article belongs to the Special Issue Recent Advances in Breast Cancer Research)

► Show Figures

Figure 1

18 pages, 3739 KiB

Open AccessArticle

A Case Series Exploration of Multi-Regional Expression Heterogeneity in Triple-Negative Breast Cancer Patients

by Qi Xu, Jaspreet Kaur, Dennis Wylie, Karuna Mittal, Hongxiao Li, Rishab Kolachina, Mohammed Aleskandarany, Michael S. Toss, Andrew R. Green, Jianchen Yang, Thomas E. Yankeelov, Shristi Bhattarai, Emiel A. M. Janssen, Jun Kong, Emad A. Rakha, Jeanne Kowalski and Ritu Aneja

Int. J. Mol. Sci. 2022, 23(21), 13322; https://doi.org/10.3390/ijms232113322 - 01 Nov 2022

Cited by 2 | Viewed by 2527

Abstract

Extensive intratumoral heterogeneity (ITH) is believed to contribute to therapeutic failure and tumor recurrence, as treatment-resistant cell clones can survive and expand. However, little is known about ITH in triple-negative breast cancer (TNBC) because of the limited number of single-cell sequencing studies on [...] Read more.

Extensive intratumoral heterogeneity (ITH) is believed to contribute to therapeutic failure and tumor recurrence, as treatment-resistant cell clones can survive and expand. However, little is known about ITH in triple-negative breast cancer (TNBC) because of the limited number of single-cell sequencing studies on TNBC. In this study, we explored ITH in TNBC by evaluating gene expression-derived and imaging-derived multi-region differences within the same tumor. We obtained tissue specimens from 10 TNBC patients and conducted RNA sequencing analysis of 2–4 regions per tumor. We developed a novel analysis framework to dissect and characterize different types of variability: between-patients (inter-tumoral heterogeneity), between-patients across regions (inter-tumoral and region heterogeneity), and within-patient, between-regions (regional intratumoral heterogeneity). We performed a Bayesian changepoint analysis to assess and classify regional variability as low (convergent) versus high (divergent) within each patient feature (TNBC and PAM50 subtypes, immune, stroma, tumor counts and tumor infiltrating lymphocytes). Gene expression signatures were categorized into three types of variability: between-patients (108 genes), between-patients across regions (183 genes), and within-patients, between-regions (778 genes). Based on the between-patient gene signature, we identified two distinct patient clusters that differed in menopausal status. Significant intratumoral divergence was observed for PAM50 classification, tumor cell counts, and tumor-infiltrating T cell abundance. Other features examined showed a representation of both divergent and convergent results. Lymph node stage was significantly associated with divergent tumors. Our results show extensive intertumoral heterogeneity and regional ITH in gene expression and image-derived features in TNBC. Our findings also raise concerns regarding gene expression based TNBC subtyping. Future studies are warranted to elucidate the role of regional heterogeneity in TNBC as a driver of treatment resistance. Full article

(This article belongs to the Special Issue Recent Advances in Breast Cancer Research)

► Show Figures

Figure 1

12 pages, 445 KiB

Open AccessArticle

Circulating miR-200 Family and CTCs in Metastatic Breast Cancer before, during, and after a New Line of Systemic Treatment

by Chiara Fischer, Andrey Turchinovich, Manuel Feisst, Fabian Riedel, Kathrin Haßdenteufel, Philipp Scharli, Andreas D. Hartkopf, Sara Y. Brucker, Laura Michel, Barbara Burwinkel, Andreas Schneeweiss, Markus Wallwiener and Thomas M. Deutsch

Int. J. Mol. Sci. 2022, 23(17), 9535; https://doi.org/10.3390/ijms23179535 - 23 Aug 2022

Cited by 6 | Viewed by 1877

Abstract

The extracellular circulating microRNA (miR)-200 regulates epithelial-mesenchymal transition and, thus, plays an essential role in the metastatic cascade and has shown itself to be a promising prognostic and predictive biomarker in metastatic breast cancer (MBC). Expression levels of the plasma miR-200 family were [...] Read more.

The extracellular circulating microRNA (miR)-200 regulates epithelial-mesenchymal transition and, thus, plays an essential role in the metastatic cascade and has shown itself to be a promising prognostic and predictive biomarker in metastatic breast cancer (MBC). Expression levels of the plasma miR-200 family were analyzed in relationship to systemic treatment, circulating tumor cells (CTC) count, progression-free survival (PFS), and overall survival (OS). Expression of miR-200a, miR-200b, miR-200c, miR-141, and miR-429, and CTC status (CTC-positive ≥ 5 CTC/7.5 mL) was assessed in 47 patients at baseline (BL), after the first completed cycle of a new line of systemic therapy (1C), and upon the progression of disease (PD). MiR-200a, miR-200b, and miR-141 expression was reduced at 1C compared to BL. Upon PD, all miR-200s were upregulated compared to 1C. At all timepoints, the levels of miR-200s were elevated in CTC-positive versus CTC-negative patients. Further, heightened miR-200s expression and positive CTC status were associated with poorer OS at BL and 1C. In MBC patients, circulating miR-200 family members decreased after one cycle of a new line of systemic therapy, were elevated during PD, and were indicative of CTC status. Notably, increased levels of miR-200s and elevated CTC count correlated with poorer OS and PFS. As such, both are promising biomarkers for optimizing the clinical management of MBC. Full article

(This article belongs to the Special Issue Recent Advances in Breast Cancer Research)

► Show Figures

Figure 1

Journal Menu

Journal Browser

Recent Advances in Breast Cancer Research

Share This Special Issue

Special Issue Editor

Special Issue Information

Keywords

Related Special Issue

Published Papers (14 papers)

Editorial

Research

Further Information

Guidelines

MDPI Initiatives

Follow MDPI