scholarly journals Evaluation of Androgen Receptor in Relation to Estrogen Receptor (AR/ER) and Progesterone Receptor (AR/PgR): A New Must in Breast Cancer?

2019 ◽  
Vol 2019 ◽  
pp. 1-6 ◽  
Author(s):  
Giuseppe Bronte ◽  
Andrea Rocca ◽  
Sara Ravaioli ◽  
Emanuela Scarpi ◽  
Massimiliano Bonafè ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Androgen Receptor ◽  
Survival Data ◽  
Epithelial Mesenchymal Transition ◽  
Case Series ◽  
Transition Process ◽  
Primary Tumors ◽  
Mesenchymal Transition ◽  
Early Primary ◽  
Patient Prognosis

Steroid nuclear receptors are known to be involved in the regulation of epithelial-mesenchymal transition process with important roles in invasion and metastasis initiation. Androgen receptor (AR) has been extensively studied, but its role in relation to breast cancer patient prognosis remains to be clarified. AR/ER ratio has been reported to be an unfavorable prognostic marker in early primary breast cancer, but its role in the patients with advanced disease has to be cleared. We retrospectively analyzed ER, PgR, and AR expression on a case series of 159 specimens of primary BC samples by using immunohistochemistry and 89 patients of these had luminal tumors for which AR and ER expression and survival data were available. For twenty-four patients both primary and metastatic tumors were available. A significantly shorter overall survival was observed in primary tumors with AR/PgR ratio ≥ 1.54 (HR = 2.27; 95% CI 1.30-3.97; p = 0.004). Similarly OS was significantly shorter when ER/PgR ratio ≥2 in primary tumors (HR = 1.89; 95% CI 1.10-3.24; p = 0.021). The analysis of the 24 patients who had biomarker determinations both in primary tumors and metastasis showed a better OS when AR/ER ratio in the metastasis was ≥ 0.90 (p = 0.022). Patients with a high AR/ER ratio in primary tumor that remained high in the metastasis had better prognosis in terms of OS (p = 0.011). Despite we suggested that the ratios AR/ER and AR/PgR could be used to identify patients with different prognosis, their real value needs to be better clarified in different BC settings through prospective studies.

scholarly journals Metaplastic breast carcinoma:series of cases and literature review

Mastology ◽  
2021 ◽  
Vol 31 ◽  
Author(s):  
Giulia Papa ◽  
Carolina Fernanda Ferreira ◽  
Luisa Damasio ◽  
Karla Calaça Kabbach Prigenzi
Keyword(s):  
Breast Cancer ◽  
Literature Review ◽  
Epithelial Mesenchymal Transition ◽  
Breast Cancer Subtype ◽  
Transition Process ◽  
Final Diagnosis ◽  
Metaplastic Carcinoma ◽  
Inclusion Criteria ◽  
Mesenchymal Transition ◽  
First Case

Introduction: Metaplastic breast carcinoma is a heterogeneous group of infrequent invasive carcinomas with aggressive behavior. It presents differentiation from the neoplastic ductal epithelium to squamous and/or sarcomatous mesenchymal component, through the epithelial-mesenchymal transition process, and may present morphology of epithelioid and fusiform cells, with possible cartilage, bone, lipomatous, fibromatous, smooth muscle or skeletal muscle differentiation, among others. Most of the cases present the triple-negative immunohistochemical profile. Objective: To report three cases of metaplastic carcinomas, with an emphasis on clinical and pathological aspects, in addition to conducting a literature review on this topic. Methods: The three cases were registered in the internal search system for reference services in breast pathology in São Paulo, between 2012 and 2019. For literature review, the keywords metaplastic carcinoma, breast, cancer, review, breast cancer subtype and pathological and clinical outcomes were used in PubMed. We found 154 articles, of which 42 were selected for full reading, based on the abstract and established inclusion criteria. After this initial selection, these articles were read and reviewed; nine articles that did not meet the inclusion criteria were excluded. Discussion: Three cases of metaplastic carcinoma with similar immunohistochemical characteristics have been reported. The first case is that of a 40-year-old patient with the diagnosis of metaplastic carcinoma producing a chondroid matrix with liposarcomatous and osteosarcomatous differentiation. The second case is that of a 50-year-old patient who presented with the final diagnosis for a fusocellular metaplastic carcinoma with lymph node metastasis. Finally, the third case described is that of a 59-year-old patient, who presented metaplastic carcinoma with chondroid differentiation. Conclusion: Metaplastic carcinoma is a rare and aggressive type of breast cancer, in which most of the patients have shorter survival and worse prognosis in relation to the other subtypes. More studies are needed in order to determine a gold standard treatment for this disease.

scholarly journals A CTC-Cluster-Specific Signature Derived from OMICS Analysis of Patient-Derived Xenograft Tumors Predicts Outcomes in Basal-Like Breast Cancer

2019 ◽  
Vol 8 (11) ◽  
pp. 1772 ◽  
Author(s):  
Hariprasad Thangavel ◽  
Carmine De Angelis ◽  
Suhas Vasaikar ◽  
Raksha Bhat ◽  
Mohit Kumar Jolly ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Epithelial Mesenchymal Transition ◽  
B Cell Lymphoma ◽  
Gene Signature ◽  
Enrichment Score ◽  
Specific Gene ◽  
Primary Tumors ◽  
Mesenchymal Transition ◽  
Patient Derived Xenograft ◽  
Pdx Models

Circulating tumor cell clusters (CTCcl) have a higher metastatic potential compared to single CTCs and predict long-term outcomes in breast cancer (BC) patients. Because of the rarity of CTCcls, molecular characterization of primary tumors that give rise to CTCcl hold significant promise for better diagnosis and target discovery to combat metastatic BC. In our study, we utilized the reverse-phase protein array (RPPA) and transcriptomic (RNA-Seq) data of 10 triple-negative BC patient-derived xenograft (TNBC PDX) transplantable models with CTCs and evaluated expression of upregulated candidate protein Bcl2 (B-cell lymphoma 2) by immunohistochemistry (IHC). The sample-set consisted of six CTCcl-negative (CTCcl−) and four CTCcl-positive (CTCcl+) models. We analyzed the RPPA and transcriptomic profiles of CTCcl− and CTCcl+ TNBC PDX models. In addition, we derived a CTCcl-specific gene signature for testing if it predicted outcomes using a publicly available dataset from 360 patients with basal-like BC. The RPPA analysis of CTCcl+ vs. CTCcl− TNBC PDX tumors revealed elevated expression of Bcl2 (false discovery rate (FDR) < 0.0001, fold change (FC) = 3.5) and reduced acetyl coenzyme A carboxylase-1 (ACC1) (FDR = 0.0005, FC = 0.3) in CTCcl+ compared to CTCcl− tumors. Genome-wide transcriptomic analysis of CTCcl+ vs. CTCcl− tumors revealed 549 differentially expressed genes associated with the presence of CTCcls. Apoptosis was one of the significantly downregulated pathways (normalized enrichment score (NES) = −1.69; FDR < 0.05) in TNBC PDX tumors associated with CTCcl positivity. Two out of four CTCcl+ TNBC PDX primary tumors had high Bcl2 expression by IHC (H-score > 34); whereas, only one of six CTCcl− TNBC PDX primary tumors met this criterion. Evaluation of epithelial-mesenchymal transition (EMT)-specific signature did not show significant differences between CTCcl+ and CTCcl− tumors. However, a gene signature associated with the presence of CTCcls in TNBC PDX models was associated with worse relapse-free survival in the publicly available dataset from 360 patients with basal-like BC. In summary, we identified the multigene signature of primary PDX tumors associated with the presence of CTCcls. Evaluation of additional TNBC PDX models and patients can further illuminate cellular and molecular pathways facilitating CTCcl formation.

scholarly journals Palladium nanoplates scotch breast cancer lung metastasis by constraining epithelial-mesenchymal transition

2020 ◽  
Author(s):  
Shunhao Wang ◽  
Jingchao Li ◽  
Mei Chen ◽  
Liting Ren ◽  
Wenya Feng ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Lung Metastasis ◽  
Transforming Growth Factor Beta ◽  
Cancer Metastasis ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Synergistic Effects ◽  
Cancer Therapeutics ◽  
Primary Tumors ◽  
Mesenchymal Transition

ABSTRACT Metastasis accounts for the majority of cancer deaths in many tumor types including breast cancer. Epithelial-mesenchymal transition (EMT) is the driving force for the occurrence and progression of metastasis, however, no targeted strategies to block the EMT program are currently available to combat metastasis. Diverse engineered nanomaterials (ENMs) have been reported to exert promising anti-cancer effects, however, no ENMs have been designed to target EMT. Palladium (Pd) nanomaterials, a type of ENM, have received substantial attention in nanomedicine due to their favorable photothermal performance for cancer therapeutics. Herein, Pd nanoplates (PdPL) were found to be preferentially biodistributed to both primary tumors and metastatic tumors. Importantly, PdPL showed a significant inhibition of lung metastasis with and without near-infrared (NIR) irradiation. Mechanistic investigations revealed that EMT was significantly compromised in breast cancer cells upon the PdPL treatment, which was partially due to the inhibition of the transforming growth factor-beta (TGF-β) signaling. Strikingly, the PdPL was found to directly interact with TGF-β proteins to diminish TGF-β functions in activating its downstream signaling, as evidenced by the reduced phosphorylation of Smad2. Notably, TGF-β-independent pathways were also involved in undermining EMT and other important biological processes that are necessary for metastasis. Additionally, NIR irradiation elicited synergistic effects on PdPL-induced inhibition of primary tumors and metastasis. In summary, these results revealed that the PdPL remarkably curbed metastasis by inhibiting EMT signaling, thereby indicating the promising potential of PdPL as a therapeutic agent for treating breast cancer metastasis.

scholarly journals Phenotypic Heterogeneity of Triple-Negative Breast Cancer Mediated by Epithelial–Mesenchymal Plasticity

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2188
Author(s):  
Barbora Kvokačková ◽  
Ján Remšík ◽  
Mohit Kumar Jolly ◽  
Karel Souček
Keyword(s):  
Breast Cancer ◽  
Tumor Cells ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Epithelial Mesenchymal Transition ◽  
Intratumoral Heterogeneity ◽  
Primary Tumors ◽  
Mesenchymal Transition ◽  
Metastatic Colonization ◽  
Evolutionarily Conserved

Triple-negative breast cancer (TNBC) is a subtype of breast carcinoma known for its unusually aggressive behavior and poor clinical outcome. Besides the lack of molecular targets for therapy and profound intratumoral heterogeneity, the relatively quick overt metastatic spread remains a major obstacle in effective clinical management. The metastatic colonization of distant sites by primary tumor cells is affected by the microenvironment, epigenetic state of particular subclones, and numerous other factors. One of the most prominent processes contributing to the intratumoral heterogeneity is an epithelial–mesenchymal transition (EMT), an evolutionarily conserved developmental program frequently hijacked by tumor cells, strengthening their motile and invasive features. In response to various intrinsic and extrinsic stimuli, malignant cells can revert the EMT state through the mesenchymal–epithelial transition (MET), a process that is believed to be critical for the establishment of macrometastasis at secondary sites. Notably, cancer cells rarely undergo complete EMT and rather exist in a continuum of E/M intermediate states, preserving high levels of plasticity, as demonstrated in primary tumors and, ultimately, in circulating tumor cells, representing a simplified element of the metastatic cascade. In this review, we focus on cellular drivers underlying EMT/MET phenotypic plasticity and its detrimental consequences in the context of TNBC cancer.

scholarly journals Constitutively Active Androgen Receptor Supports the Metastatic Phenotype of Endocrine-Resistant Hormone Receptor-Positive Breast Cancer

2020 ◽  
Author(s):  
Shaymaa Bahnassy ◽  
Tasneem Bawa-Khalfe ◽  
Hariprasad Thangavel ◽  
Maram Quttina ◽  
Ashfia Khan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Androgen Receptor ◽  
Cell Lines ◽  
Hormone Receptor ◽  
Epithelial Mesenchymal Transition ◽  
Intrinsic Resistance ◽  
Metastatic Phenotype ◽  
Mesenchymal Transition ◽  
Hormone Receptor Positive ◽  
Constitutively Active

Abstract Background: Hormone receptor positive (HR+) breast cancer (BCa) is the most frequently diagnosed subtype. Acquired and intrinsic resistance to conventional endocrine therapy (ET) commonly occurs and prompts incurable metastatic disease. Hence, ET-resistant (ET-R) HR+ BCa presents a therapeutic challenge. Previous studies show elevated androgen receptor (AR) that supports resistance to ET tamoxifen and correlates with HR+ BCa metastasis. Yet surprisingly, studies with AR-blocker enzalutamide (Enz) in ET-R HR+ BCa present conflicting results. We now report that a constitutively active, unique from canonical Enz-targeted, AR accumulates in endocrine resistant HR+ BCa cells. Methods: AR protein profiles in acquired and intrinsic ET-R HR+-BCa were defined with cell-free modification tests, in-house in-vivo SUMOylation assays, and PLA imaging. Genomic activity of native AR and modified-AR mimetic was tested with reporter assays and limited transcriptome analysis. Spheroid growth and migration studies were used to evaluate inhibitory actions of Enz and combinatorial therapy. Results: Sustained higher molecular weight SUMO-modified AR (SUMO-AR) persists in acquired and intrinsic ET-R BCa cell lines. Concurrently, SUMO isoforms and global SUMO-modified proteome also accumulates in the same cell lines. We identified AR as a novel substrate for the SUMO-E3 ligase HSPB1/Hsp27. Independent of ligand, SUMO-AR is resilient to ubiquitin-mediated proteasomal degradation, enriched in the nucleus, readily chromatin-bound, and transcriptionally active. Constitutive SUMO-AR initiates a gene-expression profile that favors epithelial-mesenchymal transition. Enz combined with a SUMO inhibitor attenuates migration and metastatic phenotype of ET-R HR+ BCa. Conclusion: Targeting both unmodified and SUMO-modified AR prevents the metastatic progression of HR+ BCa with ET-R.

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