Preclinical Advances in Theranostics for the Different Molecular Subtypes of Breast Cancer.
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ABSTRACT:
SUBMITTER: Fang H
PROVIDER: S-EPMC8111013 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The aim of the study was to determine the metabolic characteristics of saliva depending on the molecular biological subtype of breast cancer, as well as depending on the expression levels of HER2, estrogen receptors (ER), and progesterone receptors (PR). The study included 487 patients with morphologically verified breast cancer and 298 volunteers without breast pathologies. Saliva samples were obtained from all patients strictly before the start of treatment and the values of 42 biochemical indicators were determined. It has been established that the saliva of healthy volunteers and patients with various molecular biological subtypes of breast cancer differs in 12 biochemical indicators: concentrations of protein, urea, nitric oxide, malondialdehyde, total amino acid content, and activity of lactate dehydrogenase, alkaline phosphatase, gamma-glutamyltransferase, catalase, amylase, superoxide dismutase, and peroxidases. The saliva composition of patients with basal-like breast cancer differs from other subtypes in terms of the maximum number of indicators. Changes in biochemical indicators indicated an increase in the processes of lipid peroxidation and endogenous intoxication and a weakening of antioxidant protection, which correlates with the severity of the disease and the least favorable prognosis for this subtype of breast cancer. An analysis was made of the individual contribution of the expression level of HER2, estrogen, and progesterone receptors to changes in the biochemical composition of saliva. The HER2 (-)/HER2 (+) group, which should be considered as a single group, as well as ER-positive breast cancer, differ statistically significantly from the control group. For ER/PR-positive breast cancer, a more favorable ratio of saliva biochemical indicators was also noted compared to ER/PR-negative breast cancer.
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Project description:Colorectal cancer (CRC) is a heterogeneous disease. More insight into the biological diversity of CRC is needed to improve therapeutic outcomes. Established CRC cell lines are frequently used and were shown to be representative models of the main subtypes of CRC at the genomic and transcriptomic level. In the present work, we established stable, luciferase expressing derivatives from 10 well-established CRC cell lines, generated spheroids and subcutaneous xenograft tumors in nude mice, and performed comparative characterization of these model systems. Transcriptomic analyses revealed the close relation of cell lines with their derived spheroids and xenograft tumors. The preclinical model systems clustered with patient tumor samples when compared to normal tissue thereby confirming that cell-line-based tumor models retain specific characteristics of primary tumors. Xenografts showed different differentiation patterns and bioluminescence imaging revealed metastatic spread to the lungs. In addition, the models were classified according to the CMS classification system, with further sub-classification according to the recently identified two intrinsic epithelial tumor cell states of CRC, iCMS2 and iCMS3. The combined data showed that regarding primary tumor characteristics, 3D-spheroid cultures resemble xenografts more closely than 2D-cultured cells do. Furthermore, we set up a bioluminescence-based spheroid cytotoxicity assay in order to be able to perform dose-response relationship studies in analogy to typical monolayer assays. Applying the established assay, we studied the efficacy of oxaliplatin. Seven of the ten used cell lines showed a significant reduction in the response to oxaliplatin in the 3D-spheroid model compared to the 2D-monolayer model. Therapy studies in selected xenograft models confirmed the response or lack of response to oxaliplatin treatment. Analyses of differentially expressed genes in these models identified CAV1 as a possible marker of oxaliplatin resistance. In conclusion, we established a combined 2D/3D, in vitro/in vivo model system representing the heterogeneity of CRC, which can be used in preclinical research applications.
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Project description:The goal of this study was to determine whether gene expression differences exist between inflammatory breast cancers (IBC) and T stage-matched non-IBC patients stratified by hormone receptor and HER2 status. We used Affymetrix GeneChips to analyze 82 tumor samples (25 T4d patients, and 57 T4a-c patients) of newly diagnosed breast cancers. Genes that were differentially expressed between the IBC and non-IBC specimens were identified using the t test, and differential expression of gene sets was assessed using gene set analysis. Three distinct clinical subtypes of IBC and non-IBC were compared: ER-positive/HER2-normal, HER2-amplified, and ER-negative/HER2-normal. When we compared expression data from all IBC with all non-IBC, we found no significant differences after adjusting for multiple testing. When IBC and non-IBC tumors were compared by clinical subtype, however, significant differences emerged. Complement and immune system-related pathways were overexpressed in ER-positive/HER2-normal IBC. Protein translation and mTOR signaling were overexpressed in HER2-amplified IBC. Apoptosis-, neural-, and lipid metabolism-related pathways were overexpressed in ER-negative/HER2-normal IBC compared with non-IBC of the same receptor phenotype. In this T stage-matched case-control study, the survival curves of patients with IBC and non-IBC were similar for all three clinical subtypes. IBC tumors can be divided into molecular and clinical subtypes similar to those of non-IBC. Clinical subtypes of IBC show molecular differences compared with similar subtypes of non-IBC.
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Project description:We established combined 2D/3D, in vitro/in vivo model systems representing the heterogeneity of colorectal cancer (CRC) with regards to different molecular subtypes. Comparative characterization of stable luciferase expressing derivatives of well-established CRC cell lines, derived spheroids and subcutaneous xenograft tumors showed that the 3D-spheroid cultures resembled xenografts more closely than 2D-cultured cells do. The model systems can be used in preclinical research applications to study new therapy approaches and represents the biological heterogeneity of CRC.
2023-10-10 | GSE241569 | GEO
Project description:BackgroundAlthough the conversion of clinically used breast cancer biomarkers such as estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) between primary tumors and metastatic lesions is well recognized, data on whether receptor conversion has an effect on therapy management and survival in patients with metastatic breast cancer is limited. This study aimed to investigate the clinical implications of receptor conversion throughout tumor progression.MethodsIn total, 2450 patients diagnosed with metastatic breast cancer in Tianjin Medical University Cancer Institute and Hospital were analyzed and 426 female patients with available biopsy results from both primary and metastatic sites were included in this study. We investigated the alteration of ER, PR and HER2 during breast cancer progression and evaluated the therapy management and prognostic value of receptor conversion.ResultsThe conversion rates of ER, PR, and HER2 between primary tumors and metastasis were 21.1% (McNemar's test p < 0.001), 33.2% (p < 0.001), and 11.6% (p = 0.868), respectively. Evaluation of ER, PR, and HER2 status in multiple consecutive metastases revealed a change in 19.1% (p > 0.05), 23.5% (p = 0.021), and 9.8% (p > 0.05) of patients, respectively. Adjuvant therapy (chemotherapy/endocrine therapy) was related to hormone receptor conversion (p < 0.05). A statistically significant differential survival associated with hormone receptor (ER/PR) conversion (log-rank p < 0.05) was observed. In the multivariate analysis, ER conversion was an independent influence factor of survival (p < 0.05). Molecular typing conversion in primary and metastatic lesions also had a significant effect on survival (p < 0.05). We found that changing treatment based on the receptor conversion could affect clinical outcomes (p < 0.05).ConclusionsOur findings indicated that receptor conversion during breast tumor progression had a significant effect on survival. Most importantly, our findings proved that patients with receptor conversion benefited from a change in therapy.
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Project description:There is great interest in developing gene therapies for many disease indications, including cancer. However, successful delivery of nucleic acids to tumor cells is a major challenge, and in vivo efficacy is difficult to predict. Cancer theranostics is an approach combining anti-tumor therapy with imaging or diagnostic capabilities, with the goal of monitoring successful delivery and efficacy of a therapeutic agent in a tumor. Successful theranostics must maintain a high degree of anticancer targeting and efficacy while incorporating high-contrast imaging agents that are nontoxic and compatible with clinical imaging modalities. This review highlights recent advancements in theranostic strategies, including imaging technologies and genetic engineering approaches. Graphical Abstract.
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Project description:Hafnium-based nanomaterials (Hf-NMs) have attracted the interest of numerous biomedical researchers by their unique properties. Recent years have witnessed significant advancements in the field of Hafnium-based nanomaterials, particularly in the context of cancer diagnosis and treatment. However, research in this area, especially concerning the clinical application of Hafnium-based nanomaterials, has not been thoroughly reviewed. This review will cover: 1) Classification and synthesis of Hafnium-based nanomaterials including Hafnium oxide nanomaterials, Hafnium Metal-Organic Frameworks/nanoscale coordination polymers (MOFs/NCPs); 2) Hafnium-based nanomaterials act as contrast enhancement agent for cancer imaging, and hafnium-based nanomaterials used for diagnosis in cancer liquid biopsy; 3) hafnium-based nanomaterials for cancer therapy, including hafnium-based nanomaterials for radiotherapy, hafnium-based nanomaterials for photodynamic therapy, hafnium-based nanomaterials for various combined therapy; and 4) Translation, toxicity, and safety for Hf-NMs in human and preclinical animal models. More attention will be given to the clinical translation of Hf-NMs in cancer.
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Project description:Molecular subtypes of triple negative breast cancer (TNBC) are associated with variation in survival and may assist in treatment selection. However, the association of patient race or ethnicity with subtypes of TNBC and clinical outcome has not been addressed. Using nCounter Gene Expression Codesets, we classified TNBCs into subtypes: basal-like immune-activated (BLIA), basal-like immunosuppressed (BLIS), luminal androgen receptor (LAR), and mesenchymal (MES) in 48 Hispanic, 12 African-American, 21 Asian, and 34 White patients. Mean age at diagnosis was significantly associated with subtype, with the youngest mean age (50 years) in MES and the oldest mean age (64 years) in LAR (p < 0.0005). Subtype was significantly associated with tumor grade (p = 0.0012) and positive lymph nodes (p = 0.021), with a marginally significant association of tumor stage (p = 0.076). In multivariate Cox-proportional hazards modeling, BLIS was associated with worst survival and LAR with best survival. Hispanics had a significantly higher proportion of BLIS (53%, p = 0.03), whereas Asians had a lower proportion of BLIS (19%, p = 0.05) and a higher proportion of LAR (38%, p = 0.06) compared to the average proportion across all groups. These differences in proportions of subtype across racial and ethnic groups may explain differences in their outcomes. Determining subtypes of TNBC facilitates understanding of the heterogeneity of the TNBCs and provides a foundation for developing subtype-specific therapies and better predictors of TNBC prognosis for all races and ethnicities.
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Project description:Breast cancer is a heterogeneous and complex disease, a clear manifestation of this is its classification into different molecular subtypes. On the other hand, gene transcriptional networks may exhibit different modular structures that can be related to known biological processes. Thus, modular structures in transcriptional networks may be seen as manifestations of regulatory structures that tightly controls biological processes. In this work, we identify modular structures on gene transcriptional networks previously inferred from microarray data of molecular subtypes of breast cancer: luminal A, luminal B, basal, and HER2-enriched. We analyzed the modules (communities) found in each network to identify particular biological functions (described in the Gene Ontology database) associated to them. We further explored these modules and their associated functions to identify common and unique features that could allow a better level of description of breast cancer, particularly in the basal-like subtype, the most aggressive and poor prognosis manifestation. Our findings related to the immune system and a decrease in cell death-related processes in basal subtype could help to understand it and design strategies for its treatment.
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Project description:BACKGROUND:Type II diabetes and certain diabetes treatments have been observed to impact breast cancer risk. However, their associations with different breast cancer molecular subtype defined by estrogen receptor (ER)/progesterone receptor (PR)/HER2 status are unclear. METHODS:We conducted a retrospective multi-center population-based case-case study consisting of 4,557 breast cancer cases to evaluate the impact of type II diabetes and diabetes medications on the risk of different breast cancer molecular subtypes [ER+/HER2-, ER+/HER2+, triple negative (ER-/PR-/HER2-), and HER2 overexpressing (H2E, ER-/PR-/HER2+)]. Using ER+/HER2- cases as the reference group, we estimated ORs and corresponding 95% confidence intervals (CI) for each subtype using polytomous logistic regression. RESULTS:Compared with those without a diabetes history, women with type II diabetes had a 38% (95% CI, 1.01-1.89) increased odds of triple-negative breast cancer (TNBC). Current and longer term recent metformin use (13-24 months of treatment within the 24-month period prior to breast cancer diagnosis) was associated with elevated odds of TNBC (OR = 1.54; 95% CI, 1.07-2.22 and OR = 1.80; 95% CI, 1.13-2.85, respectively). CONCLUSIONS:The odds of having a triple-negative rather than ER+/HER2- breast cancer is greater for women with type II diabetes, and particularly for those who were users of metformin. This finding is supported by some preclinical data suggesting that diabetes may be more strongly associated with risk of triple-negative disease. IMPACT:Our study provides novel evidence regarding potential differential effects of type II diabetes and metformin use on risk of different molecular subtypes of breast cancer.
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