Integrative Analysis of Breast Cancer Cells Reveals an Epithelial-Mesenchymal Transition Role in Adaptation to Acidic Microenvironment

Early ducts of breast tumors are unequivocally acidic. High rates of glycolysis combined with poor perfusion lead to a congestion of acidic metabolites in the tumor microenvironment, and pre-malignant cells must adapt to this acidosis to thrive. Adaptation to acidosis selects cancer cells that can thrive in harsh conditions and are capable of outgrowing the normal or non-adapted neighbors. This selection is usually accompanied by phenotypic change. Epithelial mesenchymal transition (EMT) is one of the most important switches correlated to malignant tumor cell phenotype and has been shown to be induced by tumor acidosis. New evidence shows that the EMT switch is not a binary system and occurs on a spectrum of transition states. During confirmation of the EMT phenotype, our results demonstrated a partial EMT phenotype in our acid-adapted cell population. Using RNA sequencing and network analysis we found 10 dysregulated network motifs in acid-adapted breast cancer cells playing a role in EMT. Our further integrative analysis of RNA sequencing and SILAC proteomics resulted in recognition of S100B and S100A6 proteins at both the RNA and protein level. Higher expression of S100B and S100A6 was validated in vitro by Immunocytochemistry. We further validated our finding both in vitro and in patients' samples by IHC analysis of Tissue Microarray (TMA). Correlation analysis of S100A6 and LAMP2b as marker of acidosis in each patient from Moffitt TMA approved the acid related role of S1...
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research

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Abstract Breast and mammary epithelial cells experience different local environments during tissue development and tumorigenesis. Microenvironmental heterogeneity gives rise to distinct cell regulatory states whose identity and importance are just beginning to be appreciated. Cellular states diversify when clonal three-dimensional (3D) spheroids are cultured in basement membrane, and one such state is associated with stress tolerance and poor response to anticancer therapeutics. Here, we found that this state was jointly coordinated by the NRF2 and p53 pathways, which were costabilized by spontaneous oxidative str...
Source: Science Signaling - Category: Biomedical Science Authors: Tags: Sci Signal Source Type: research
Breast and mammary epithelial cells experience different local environments during tissue development and tumorigenesis. Microenvironmental heterogeneity gives rise to distinct cell regulatory states whose identity and importance are just beginning to be appreciated. Cellular states diversify when clonal three-dimensional (3D) spheroids are cultured in basement membrane, and one such state is associated with stress tolerance and poor response to anticancer therapeutics. Here, we found that this state was jointly coordinated by the NRF2 and p53 pathways, which were costabilized by spontaneous oxidative stress within 3D cult...
Source: Signal Transduction Knowledge Environment - Category: Science Authors: Tags: STKE Research Articles Source Type: news
Authors: Karanis M, Koksal H, Ates E, Dogru O Abstract The aim of this study was to evaluate the clinical importance of fibulin-5, which has been shown to display tumour-promoting and tumour-protective functions in breast lesions. Sixty-two breast cancer patients, 19 patients with fibroadenoma, and 15 healthy breast tissues were enrolled. Forty-seven patients had invasive ductal carcinoma (IDC) (12 of them also had in situ carcinoma DCIS), and 15 had invasive lobular carcinoma (ILC). A scoring system from 0 to 4 was used to evaluate the fibulin-5 staining according to the percentage of stained cells. The median val...
Source: Polish Journal of Pathology - Category: Pathology Tags: Pol J Pathol Source Type: research
Mittal Miller The mechanisms that drive ductal carcinoma in situ (DCIS) progression to invasive cancer are not clear. Studying DCIS progression in humans is challenging and not ethical, thus necessitating the characterization of an animal model that faithfully resembles human disease. We have characterized a canine model of spontaneous mammary DCIS and invasive cancer that shares histologic, molecular, and diagnostic imaging characteristics with DCIS and invasive cancer in women. The purpose of the study was to identify markers and altered signaling pathways that lead to invasive cancer and shed light on early m...
Source: Cancers - Category: Cancer & Oncology Authors: Tags: Article Source Type: research
In this study, we aimed to evaluate the prognostic significance of CTSV in DCIS. METHODS: CTSV protein expression was immunohistochemically assessed in a well-characterised and annotated cohort of DCIS comprising pure DCIS (n=776) and DCIS coexisting with IBC (n=239). CTSV expression was analysed in tumour cells and surrounding stroma, including its association with clinicopathological parameters and outcome. RESULTS: In pure DCIS, high CTSV expression was observed in 29% of epithelial tumour cells and 20% of surrounding stroma. High expression in both components was associated with features of poor prognosis inc...
Source: Clinical Genitourinary Cancer - Category: Cancer & Oncology Authors: Tags: J Clin Pathol Source Type: research
ConclusionThis demonstrates procoagulant phenotypic changes occur in fibroblasts at the preinvasive stage. Fibroblast procoagulant phenotype is associated with aggressive breast cancer subtypes and reduced survival. Coagulation may be a therapeutic target in breast cancer.
Source: Cancer Medicine - Category: Cancer & Oncology Authors: Tags: ORIGINAL RESEARCH Source Type: research
Biological markers that could predict the progression of ductal carcinoma in-situ (DCIS) to invasive breast cancer (IDC) are required urgently for personalized therapy for patients diagnosed with DCIS. As stroma was invaded by malignant cells, perturbed stromal-epithelial interactions would bring about tissue remodeling. With the specific expression of the fibroblast activation protein-alpha (FAP-a), Carcinoma-associated fibroblasts (CAFs) are the main cell populations in the remodeled tumor stroma. Golgi phosphoprotein 3 (GOLPH3), a documented oncogene possessing potent transforming capacity, is not only up-regulated in m...
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
CONCLUSIONS: There were no specific MRI imaging characteristics of high-risk lesions to predict malignancy upgrade. Therefore, surgical excision is recommended for high-risk lesions, especially ADH or lobular neoplasia. PMID: 31838725 [PubMed - as supplied by publisher]
Source: Breast Cancer - Category: Cancer & Oncology Authors: Tags: Breast Cancer Source Type: research
Mucinous lesions of the breast encompass a range of benign and malignant entities characterized by extracellular mucin production. Increased sampling of mammary calcifications has identified a range of mucocele-like lesions, which are associated with benign proliferative and atypical intraductal epithelial proliferation ranging in architectural complexity from flat epithelial atypia to ductal carcinoma in situ. Mucinous carcinoma is a unique histologic subtype of breast cancer with a good prognosis.
Source: Diagnostic Histopathology - Category: Pathology Authors: Tags: Mini-symposium: Breast Pathology Source Type: research
AbstractThe risk of radiotherapy-induced malignancies (RIMs) is a concern when treating Li –Fraumeni syndrome (LFS) or Li–Fraumeni Like (LFL) patients. However, the type ofTP53 pathogenic germline variant may possibly influence this risk.TP53 p.R337H mutation is particularly prevalent in Brazil. We aimed to evaluate the outcomes of patients with pathogenicTP53 variants treated for localized breast cancer in a Brazilian cohort. We evaluated retrospectively a cohort of patients with germlineTP53 pathogenic variants treated for localized breast cancer between December 1999 and October 2017. All patients were follo...
Source: Familial Cancer - Category: Cancer & Oncology Source Type: research
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