Dataset Information

Sodium accumulation in breast cancer predicts malignancy and treatment response.

ABSTRACT:

Background

Breast cancer remains a leading cause of death in women and novel imaging biomarkers are urgently required. Here, we demonstrate the diagnostic and treatment-monitoring potential of non-invasive sodium (²³Na) MRI in preclinical models of breast cancer.

Methods

Female Rag2^-/- Il2rg^-/- and Balb/c mice bearing orthotopic breast tumours (MDA-MB-231, EMT6 and 4T1) underwent MRI as part of a randomised, controlled, interventional study. Tumour biology was probed using ex vivo fluorescence microscopy and electrophysiology.

Results

²³Na MRI revealed elevated sodium concentration ([Na⁺]) in tumours vs non-tumour regions. Complementary proton-based diffusion-weighted imaging (DWI) linked elevated tumour [Na⁺] to increased cellularity. Combining ²³Na MRI and DWI measurements enabled superior classification accuracy of tumour vs non-tumour regions compared with either parameter alone. Ex vivo assessment of isolated tumour slices confirmed elevated intracellular [Na⁺] ([Na⁺]_i); extracellular [Na⁺] ([Na⁺]_e) remained unchanged. Treatment with specific inward Na⁺ conductance inhibitors (cariporide, eslicarbazepine acetate) did not affect tumour [Na⁺]. Nonetheless, effective treatment with docetaxel reduced tumour [Na⁺], whereas DWI measures were unchanged.

Conclusions

Orthotopic breast cancer models exhibit elevated tumour [Na⁺] that is driven by aberrantly elevated [Na⁺]_i. Moreover, ²³Na MRI enhances the diagnostic capability of DWI and represents a novel, non-invasive biomarker of treatment response with superior sensitivity compared to DWI alone.

SUBMITTER: James AD

PROVIDER: S-EPMC9296657 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Sodium accumulation in breast cancer predicts malignancy and treatment response.

James Andrew D AD Leslie Theresa K TK Kaggie Joshua D JD Wiggins Laura L Patten Lewis L Murphy O'Duinn John J Langer Swen S Labarthe Marie-Christine MC Riemer Frank F Baxter Gabrielle G McLean Mary A MA Gilbert Fiona J FJ Kennerley Aneurin J AJ Brackenbury William J WJ

British journal of cancer 20220425 2

<h4>Background</h4>Breast cancer remains a leading cause of death in women and novel imaging biomarkers are urgently required. Here, we demonstrate the diagnostic and treatment-monitoring potential of non-invasive sodium (<sup>23</sup>Na) MRI in preclinical models of breast cancer.<h4>Methods</h4>Female Rag2<sup>-/-</sup> Il2rg<sup>-/-</sup> and Balb/c mice bearing orthotopic breast tumours (MDA-MB-231, EMT6 and 4T1) underwent MRI as part of a randomised, controlled, interventional study. Tumour ...[more]

PMID: 35462561

Similar Datasets

Project description:BackgroundMore than 50% of cancer patients are recommended to receive radiotherapy. Recommendations are based mainly on clinical and pathological factors and not intrinsic tumour radio-sensitivity. Use of radiotherapy according to predictive markers would potentially reduce costly over-treatment, and improve the treatment risk-benefit ratio and cancer outcomes. Tumour expression of the 26S proteasome has been reported to predict radiotherapy response: low expression was associated with higher rates of local recurrence after radiotherapy, suggesting that low proteasome expression and activity was associated with radio-resistance. However, this conclusion is at odds with the emerging use of proteasome inhibitors as radio-sensitizers. Our aim was to further analyse the relevance of 26S proteasome expression, focussing specifically on the PSMD9 subunit, in the largest clinical cohort to date, and to investigate the functional role of PSMD9 in radio-sensitivity in breast cancer cell lines.MethodsWe examined expression of PSMD9 using immunohistochemistry in a cohort of 157 breast cancer patients, including 32 cases (20.4%) that subsequently developed local recurrences. The value of expression as a prognostic or radiotherapy predictive marker was tested using Kaplan-Meier and Cox regression analyses. PSMD9 function was examined in breast cancer cell lines MCF7 and MDA-MB-231 using siRNA knock-downs and colony forming assays after irradiation.ResultsLow tumour PSMD9 expression was significantly associated with a reduced incidence of local recurrence in patients receiving adjuvant radiotherapy (univariate log rank p = 0.02; multivariate regression p = 0.009), but not in those treated without radiotherapy, suggesting that low PSMD9 expression was associated with relative tumour radio-sensitivity. In support of this, reduction of PSMD9 expression using siRNA in breast cancer cell lines in vitro sensitized cells to radiotherapy.ConclusionsWe conclude that PSMD9 expression may predict radiotherapy benefit, with low expression indicative of relative radio-sensitivity, the opposite of previous reports relating to 26S proteasome expression. Our conclusion is compatible with use of proteasome inhibitors as radio-sensitizers, and highlights PSMD9 as a potential target for radio-sensitizing drugs.

Project description:Breast cancer (BRCA) is one of the most common malignancies encountered in women worldwide. Lipid metabolism has been found to be involved in cancer progression. Steroidogenic acute regulatory protein‑related lipid transfer 4 (STARD4) is an important cholesterol transporter involved in the regulatory mechanism of intracellular cholesterol homeostasis. However, to the best of our knowledge, the molecular functions of STARD4 in BRCA are unclear. Immunohistochemical staining and public dataset analysis were performed to investigate the expression levels of STARD4 in BRCA. In the present study, high expression of STARD4 was identified in BRCA samples and higher STARD4 expression was significantly associated with shorter distant metastasis‑free survival time in patients with BRCA, which indicated that STARD4 may be associated with BRCA progression. Cell cytometry system Celigo® analysis, Cell Counting K‑8 assays, flow cytometry, wound healing assays and transwell assays were used to investigate the effects of STARD4 knockdown on proliferation, cell cycle, apoptosis and migration in BRCA cells. Loss‑of‑function assays demonstrated that STARD4 acted as an oncogene to promote proliferation and cell cycle progression, while suppressing apoptosis in BRCA cells in vitro and in vivo. Furthermore, knockdown of STARD4 significantly suppressed BRCA metastasis. To assess the mechanism of action of STARD4, microarray analysis was performed following STARD4 knockdown in MDA‑MB‑231 cells. The data were analyzed in detail using bioinformatics, and a series of genes, including E74 like ETS transcription factor 1, cAMP responsive element binding protein 1 and p21 (RAC1) activated kinase 2, which have been previously reported to be crucial genes implicated in the malignant phenotype of cancer cells, were identified to be regulated by STARD4. Loss‑of function assays demonstrated that knockdown of STARD4 suppressed BRCA proliferation and migration. These findings suggested that STARD4 had an oncogenic effect in human BRCA progression.

Project description:Background: Breast cancer (BCa) is a heterogeneous disease requiring precise diagnostics to guide effective treatment. Current assays fail to adequately address the complex biology of BCa subtypes/risk groups and accurately predict responses to treatments like antibody-drug conjugates (ADCs). To address these limitations, we developed and validated a novel diagnostic, prognostic, and predictive tool, mFISHseq. Methods: Our approach, mFISHseq, integrates multiplexed RNA fluorescent in situ hybridization with RNA-sequencing, guided by laser capture microdissection. This technique ensures tumor purity, allows unbiased profiling of whole transcriptome data, and explicitly quantifies intratumoral heterogeneity. Results: In a retrospective cohort study involving 1,082 FFPE breast tumors, mFISHseq demonstrated high analytical validity with 93% accuracy compared to immunohistochemistry across training and test sets. Our consensus subtyping approach provided near-perfect concordance with other molecular classifiers (κ > 0.85) and reclassified 30% of samples into subtypes with distinct prognostic implications. Consensus risk groups mitigated misclassification of single samples and provided prognostic information about both early and late relapse. High risk patients had enriched innate and adaptive immune signatures, which predicted response to neoadjuvant immunotherapy. Furthermore, we identified patients responsive to ADCs, as evidenced by a 19-feature classifier for T-DM1 sensitivity, validated on the multicenter, phase II, prospective I-SPY2 trial. To demonstrate the clinical potential, we deployed mFISHseq as a research use only test on 48 patients, revealing insights into the efficacy of novel targeted therapies, such as CDK4/6 inhibitors, immune checkpoint inhibitors, and ADCs. Conclusion: The mFISHseq method solves a long-standing challenge in the precise diagnosis and classification of BCa subtypes/prognostic risk groups, and allows accurate response prediction for patients, including those treated with immunotherapies and ADCs.

Dataset Information

Sodium accumulation in breast cancer predicts malignancy and treatment response.

Background

Methods

Results

Conclusions

Publications

Sodium accumulation in breast cancer predicts malignancy and treatment response.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets