Sulfated Hyaluronan Modulates the Functional Properties and Matrix Effectors Expression of Breast Cancer Cells with Different Estrogen Receptor Status

Hyaluronan (HA) is an extracellular matrix glycosaminoglycan (GAG) that plays a pivotal role in breast cancer. While HA is the only GAG not normally substituted with sulfate groups, sulfated hyaluronan (sHA) has previously been used in studies with promising antitumor results. The aim of the present study was to evaluate the effects sHA fragments have on breast cancer cells with different estrogen receptor (ER) status. To this end, ERα-positive MCF-7, and ERβ-positive MDA-MB-231 cells were treated with non-sulfated HA or sHA fragments of 50 kDa. The functional properties of the breast cancer cells and the expression of key matrix effectors were investigated. According to the results, sHA attenuates cell proliferation, migration, and invasion, while increasing adhesion on collagen type I. Furthermore, sHA modulates the expression of epithelial-to-mesenchymal transition (EMT) markers, such as e-cadherin and snail2/slug. Additionally, sHA downregulates matrix remodeling enzymes such as the matrix metalloproteinases MT1-MMP, MMP2, and MMP9. Notably, sHA exhibits a stronger effect on the breast cancer cell properties compared to the non-sulfated counterpart, dependent also on the type of cancer cell type. Consequently, a deeper understanding of the mechanism by which sHA facilitate these processes could contribute to the development of novel therapeutic strategies.

Integrative multiomics-histopathology analysis for breast cancer classification

Histopathologic evaluation of biopsy slides is a critical step in diagnosing and subtyping breast cancers. However, the connections between histology and multi-omics status have never been systematically explored or interpreted. We developed weakly supervised deep learning models over hematoxylin-and-eosin-stained slides to examine the relations between visual morphological signal, clinical subtyping, gene expression, and mutation status in breast cancer. We first designed fully automated models for tumor detection and pathology subtype classification, with the results validated in independent cohorts (area under the receiver operating characteristic curve ≥ 0.950). Using only visual information, our models achieved strong predictive performance in estrogen/progesterone/HER2 receptor status, PAM50 status, and TP53 mutation status. We demonstrated that these models learned lymphocyte-specific morphological signals to identify estrogen receptor status. Examination of the PAM50 cohort revealed a subset of PAM50 genes whose expression reflects cancer morphology. This work demonstrates the utility of deep learning-based image models in both clinical and research regimes, through its ability to uncover connections between visual morphology and genetic statuses.

The Future Role of PET Imaging in Metastatic Breast Cancer

Background: A variety of therapeutic approaches are employed to treat patients suffering from breast cancer. Likewise, a broad spectrum of imaging ligands has been introduced for non-invasive PET/CT imaging to enable comprehensive tumor characterization and more accurate response evaluation. Summary: In recent years, novel radioactively labelled ligands have been developed for PET/CT imaging in metastatic breast cancer. One promising tracer is [18F]fluoroestradiol, which was recently approved by the Food and Drug Administration. It can be used for a whole-body assessment of estrogen receptor status. Another radionuclide currently under development is [68Ga]Ga-FAPI. In addition to new radionuclides, the field of application for existing tracers like [18F]fluorodeoxyglucose (FDG) were broadened. It has been shown that an early therapeutic response to various therapies can be detected by [18F]FDG PET/CT, which leads to early treatment optimization. Key Message: In this review, we highlighted new tracers and applications of PET/CT imaging as well as therapeutic approaches in patients with advanced breast cancer. Furthermore, we give an outlook on the application of artificial intelligence, immunoPET and liquid biopsy.

Breast cancer treatment and outcomes at Cape Coast Teaching Hospital, Ghana

Objectives: This study sought to determine the presentation, treatment and outcomes of breast cancer among women in Cape Coast, Ghana.Design: Retrospective medical record reviewSetting: Cape Coast Teaching Hospital, Cape Coast, GhanaParticipants: Female breast cancer patientsInterventions: NoneMain outcome measures: Proportion of female breast cancer patients presenting with advanced disease.Results: Approximately 84% of women had a primary presentation of breast cancer, with metastatic disease present in 34% of patients. Surgical management mainly involved partial mastectomy (21.7%) and total mastectomy (78.6%), with the most common postoperative complications being surgical site infections (3.8%). Non-surgical management involved chemotherapy, radiation therapy and anti-estrogen therapy, with Stage 3 and 4 patients twofold more likely to receive neoadjuvant chemotherapy than earlier stages (OR= 2.0 95% CI (1.4, 3.0, p<0.001). Grade 1 cancers were diagnosed in 11.0%, Grade 2 in 43.8%, and Grade 3 in 45.2%. The mean cancer size was 6.5 centimetres (range 1.5 to 20.0). Lymphatic vascular invasion was present in 59/125 (47.2%), estrogen receptor status was positive in 32.6%, progesterone receptors were positive in 22.1%, and Her-2/neu was positive in 32.6%. Triple-negative breast cancer was identified in 41/89 (46.1%).Conclusions: Women with breast cancer typically present to the Cape Coast Teaching Hospital with advanced stage disease and experience poor outcomes.

Mitochondrial estrogen receptors alter mitochondrial priming and response to endocrine therapy in breast cancer cells

Breast cancer is the most common cancer with a high rate of mortality and morbidity among women worldwide. Estrogen receptor status is an important prognostic factor and endocrine therapy is the choice of first-line treatment in ER-positive breast cancer. However, most tumors develop resistance to endocrine therapy. Here we demonstrate that BH3 profiling technology, in particular, dynamic BH3 profiling can predict the response to endocrine therapy agents as well as the development of acquired resistance in breast cancer cells independent of estrogen receptor status. Immunofluorescence analysis and subcellular fractionation experiments revealed distinct ER-α and ER-β subcellular localization patterns in breast cancer cells, including mitochondrial localization of both receptor subtypes. shRNA-mediated depletion of ER-β in breast cancer cells led to resistance to endocrine therapy agents and selective reconstitution of ER-β in mitochondria restored sensitivity. Notably, mitochondria-targeted ER-α did not restore sensitivity, even conferred further resistance to endocrine therapy agents. In addition, expressing mitochondria-targeted ER-β in breast cancer cells resulted in decreased mitochondrial respiration alongside increased total ROS and mitochondrial superoxide production. Furthermore, our data demonstrated that mitochondrial ER-β can be successfully targeted by the selective ER-β agonist Erteberel. Thus, our findings provide novel findings on mitochondrial estrogen signaling in breast cancer cells and suggest the implementation of the dynamic BH3 technique as a tool to predict acquired endocrine therapy resistance.

MiR-21 and mRNA PTEN Expression Levels and Biomarker Potential in Breast Cancer

MiR-21 has been linked to tumorigenesis, development, and metastasis in tumor pathogenesis. All human cancers, including breast cancer, have increased expression of MiR-21, which is the only miRNA that has increased expression. PTEN expression was found to be reduced in the majority of solid tumors, including breast cancer. Since lymph node metastatic factors, estrogen receptor status, tumor grade, and tumor node metastasis (TNM) all decreased PTEN expression, the PTEN expression profile may be a very useful prognostic marker in breast cancer. PTEN inhibits PIP3 (phosphatidylinositol 3,4,5-triphosphate) activity by having protein phosphatase and lipid phosphatase activity that is the polar opposite of PI3K (Phosphatidyl Inositol 3-Kinase). The aim of this research was to see how often miR-21 and mRNA PTEN were expressed at different stages of breast cancer and whether they could be used as prognostic markers. This type of research is an observational study with a cross-sectional design. The sample size of 43 people came from breast cancer patients. Analysis of miR-21 expression and mRNA PTEN using Real-Time qPCR. The results showed that miR-21 expression increased 1.32 times at an advanced stage compared to an early stage, while mRNA PTEN expression decreased 1.33 fold at an advanced stage compared to an early stage. According to the findings, miR-21 expression in the blood plasma of breast cancer patients was upregulated at an advanced stage compared to an early stage and downregulated mRNA PTEN expression. MiR-21 which is increased at an advanced stage has the potential to be a poor prognostic marker at the stage of breast cancer. The change in miR-21 expression can be a good candidate as a molecular prognostic marker and for future research the role of miR-21 in breast cancer progression will further enrich the scientific repertoire, especially in the health and clinical fields.