scholarly journals Molecular heterogeneity in breast carcinoma cells with increased invasive capacities

2020 ◽  
Vol 54 (1) ◽  
pp. 103-118
Author(s):  
Giulia Negro ◽  
Bertram Aschenbrenner ◽  
Simona Kranjc Brezar ◽  
Maja Cemazar ◽  
Andrej Coer ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Breast Carcinoma ◽  
Hormone Receptor ◽  
Breast Cancer Cells ◽  
Triple Negative ◽  
Carcinoma Cells ◽  
Her2 Positive ◽  
Cancer Subtypes ◽  
Breast Carcinoma Cells ◽  
Hormone Receptor Positive

AbstractBackgroundMetastatic progression of breast cancer is still a challenge in clinical oncology. Therefore, an elucidation how carcinoma cells belonging to different breast cancer subtypes realize their metastatic capacities is needed. The aim of this study was to elucidate a similarity of activated molecular pathways underlying an enhancement of invasiveness of carcinoma cells belonging to different breast carcinoma subtypes.Materials and methodsIn order to reach this aim, parental and invasive (INV) MDA-MB-231 (triple-negative), T47D (hormone receptor-positive), and Au565 (Her2-positive) breast carcinoma cells were used and their molecular phenotypes were compared using a proteomic approach.ResultsIndependently from breast cancer subtypes, INV cells have demonstrated fibroblast-like morphology accompanied by enhancement of invasive and migratory capacities, increased expression of cancer stem cell markers, and delayed tumor growth in in vivo animal models. However, the global proteomic analysis has highlighted that INV cells were different in protein expressions from the parental cells, and Her2-positive Au565-INV cells showed the most pronounced molecular differences compared to the triple-negative MDA-MB-231-INV and hormone receptor-positive T47D-INV cells. Although Au565-INV breast carcinoma cells possessed the highest number of deregulated proteins, they had the lowest overlapping in proteins commonly expressed in MDA-MB-231-INV and T47D-INV cells.ConclusionsWe can conclude that hormone receptor-positive cells with increased invasiveness acquire the molecular characteristics of triple-negative breast cancer cells, whereas Her2-positive INV cells specifically changed their own molecular phenotype with very limited partaking in the involved pathways found in the MDA-MB-231-INV and T47D-INV cells. Since hormone receptor-positive invasive cells share their molecular properties with triple-negative breast cancer cells, we assume that these types of metastatic disease can be treated rather equally with an option to add anti-hormonal agents. In contrast, Her2-positive metastasis should be carefully evaluated for more effective therapeutic approaches which are distinct from the triple-negative and hormone-positive metastatic breast cancers.

scholarly journals Distinct Somatic Alteration Features Identified by Gene Panel Sequencing in Korean Triple-Negative Breast Cancer with High Ki67 Expression

Diagnostics ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 416
Author(s):  
Woo Young Sun ◽  
Jina Lee ◽  
Bong Kyun Kim ◽  
Jong Ok Kim ◽  
Joonhong Park
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Hormone Receptor ◽  
Mutation Frequency ◽  
Triple Negative ◽  
Genetic Difference ◽  
Her2 Positive ◽  
Ki 67 ◽  
Hormone Receptor Positive ◽  
Somatic Alteration

This study aimed to clarify the genetic difference between Korean triple-negative breast cancer (TNBC) and other breast cancer (BC) subtypes. TNBC was defined as the absence of hormonal receptors and human epidermal growth factor receptor 2 (HER2) amplification. DNA panel of the Ion Torrent Oncomine Comprehensive Assay (OCA) v3 was performed to identify somatic alteration in 48 specimens. In a total of 102 alterations (37 nonsense, 35 missense, 8 frameshift and 22 amplifications), 30 nucleotide alterations (24 nonsense, 1 missense, and 5 frameshift) were newly identified. The eight most commonly altered genes were PIK3CA, TP53, ERBB2, BRCA2, FANCD2, AKT1, BRCA1, and FANCA. TNBC had significantly lower mutation frequency in PIK3CA (TNBC vs. hormone receptor-positive and HER2-negative BC [HRPBC], p = 0.009), but higher mutation frequency in TP53 (TNBC vs. HRPBC, p = 0.036; TNBC vs. hormone receptor-positive and HER2- positive BC [HHPBC], p = 0.004). TNBC showed frequently higher Ki-67 expression than any positive BC (p = 0.004) due to HRPBC (p < 0.001). TNBC with high Ki-67/unmutated PIK3CA/mutated TP53 appears at a younger age (52.2 ± 7.6 years), compared to other subtypes (63.7 ± 11.0 years). TNBC with high Ki-67/unmutated PIK3CA/mutated TP53 may be related to relatively early onset BCThese findings demonstrate the genomic heterogeneity between TNBC and other BC subtypes and could present a new approach for molecular targeted therapy in TNBC patients.

Imatinib-induced changes in gene expression and the metastatic potential of human breast carcinoma cells

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 1074-1074
Author(s):  
A. Lorico ◽  
F. Anzanello ◽  
G. Rappa
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Breast Carcinoma ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Carcinoma Cells ◽  
Myelogenous Leukemia ◽  
Breast Carcinoma Cells

1074 Background: Imatinib mesylate (imatinib) is a potent and selective inhibitor of the tyrosine kinases, Bcr-Abl, c-Kit and platelet-derived growth factor receptors (PDGFRs). Since its advent for the successful treatment of chronic myelogenous leukemia in 2001, the clinical efficacy of imatinib has been investigated in many other human malignancies, including breast cancer. Based on recent reports that chemotherapy selects more invasive and metastasizing cells, we have hypothesized that exposure of breast cancer cells to imatinib could enhance their malignant behavior. Methods: MA-11 breast carcinoma cells, originating from bone marrow micrometastases, were exposed to imatinib in vitro for seven days. After four days of recovery in drug-free medium, biological properties and gene expression pattern were compared with those of the parental cell line. In a separate set of experiments, the effects of in vivo administration of imatinib to athymic nude (nu/nu) mice carrying MA-11 tumors were investigated. Results: In vitro, imatinib treatment increased the motility and invasiveness of the breast cancer cells, and induced over-expression of drug transporters and of a set of genes associated with aggressive and metastatic behavior (Table). In vivo, nu/nu mice subcutaneously implanted with MA-11 cells and treated with nine daily intraperitoneal doses of 60 mg/Kg imatinib developed with greater frequency distant organ metastases vs. control mice implanted with MA-11 and treated with the vehicle alone. Conclusions: Our data caution against the clinical use of imatinib in breast cancer; imatinib-selected breast cancer cells represent an important tool to investigate the pro-metastatic role of differentially expressed genes. [Table: see text] No significant financial relationships to disclose.

CD24 expression and breast cancer stem cell phenotype

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 11106-11106
Author(s):  
G. Rappa ◽  
F. Anzanello ◽  
A. Lorico
Keyword(s):  
Breast Cancer ◽  
Stem Cell ◽  
Breast Carcinoma ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Carcinoma Cells ◽  
Cell Phenotype ◽  
Cell Cycle Distribution ◽  
Breast Carcinoma Cells ◽  
The Relationship

11106 Background: Several studies suggest the existence of breast cancer-initiating cells (BCIC), responsible for tumor development and progression. Initial reports that only the CD44+CD24−/low subpopulation contains BCIC have been challenged by subsequent studies. We examined the relationship between CD24 and biological properties of breast cancer cells. Methods: MA-11 breast carcinoma cells, originating from bone marrow micrometastases, are CD44+ and have an heterogeneous expression of CD24 (214,000/cell; range 0–1,120,000). We have previously reported that upon in vitro culture as mammospheres under stem cell-like conditions, MA-11 cells acquired increased tumorigenicity and a CD44+CD24−/low phenotype. We have now investigated the relationship between CD24 expression and tumorigenicity in the MA-11 model. Results: Upon passage of MA-11 mammospheres in adherent culture, cells rapidly re-expressed CD 24. The rapid increase in CD24 was consistent with antigen up-regulation, not selection of CD24−/low cells. Exposure of adherent MA-11 cells to imatinib for 72h resulted in a reversible decrease in CD24 from 214,000 to 15,800/cell. CD44+CD24−/low cells, sorted by flow cytometry, generated CD44+CD24high, and CD44+CD24highgenerated CD44+CD24−/low. Immediately after sorting, >90% CD44+CD24−/low cells were in G0/G1. After 24–48 h in culture, cell cycle distribution, growth rate and invasiveness of the sorted cell populations were equivalent. Upon injection and s.c. growth, CD24 expression of CD44+CD24−/low populations and clones increased from 10,000 to 220,000/cell. Similarly, CD44+CD24−/low clones derived from human MCF-7 breast carcinoma cells formed tumors containing >99% CD44+CD24high cells. The average number of CD24 per cell was equivalent for tumors formed upon injection of CD44+CD24−/low, CD44+CD24+, mammosphere-derived cells or parental adherent MA-11 cells. The tumorigenic potentials of sorted CD44+CD24−/low, CD44+CD24−/lowsub-populations and clones in nu/nu mice were equivalent. Conclusions: CD44+CD24−/low breast cancer cells are not associated with increased tumorigenicity; the high CD24 level of mouse xenografts derived from both CD44+CD24−/low and CD44+CD24hi breast cancer cells suggests an important role for CD24 in tumor growth. No significant financial relationships to disclose.

Response-Guided Neoadjuvant Chemotherapy for Breast Cancer

2013 ◽  
Vol 31 (29) ◽  
pp. 3623-3630 ◽  
Author(s):  
Gunter von Minckwitz ◽  
Jens Uwe Blohmer ◽  
Serban Dan Costa ◽  
Carsten Denkert ◽  
Holger Eidtmann ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Neoadjuvant Chemotherapy ◽  
Early Breast Cancer ◽  
Hormone Receptor ◽  
Triple Negative ◽  
Pathologic Complete Response ◽  
Exploratory Analysis ◽  
Her2 Positive ◽  
Luminal B ◽  
Hormone Receptor Positive

Purpose We investigated disease-free survival (DFS) and overall survival (OS) after response-guided neoadjuvant chemotherapy in patients with early breast cancer. Patients and Methods We treated 2,072 patients with two cycles of docetaxel, doxorubicin, and cyclophosphamide (TAC) and randomly assigned early responders to four (n = 704) or six (n = 686) additional TAC cycles, and early nonresponders to four cycles of TAC (n = 321) or vinorelbine and capecitabine (NX; n = 301) before surgery. Results DFS was longer in early responders receiving TAC × 8 than in those receiving TAC × 6 (hazard ratio [HR], 0.78; 95% CI, 0.62 to 0.97; P = .026), and in early nonresponders receiving TAC-NX than in those receiving TAC × 6 (HR, 0.59; 95% CI, 0.49 to 0.82; P = .001). Exploratory analysis showed that DFS after response-guided chemotherapy (TAC × 8 or TAC-NX) was significantly longer (HR, 0.71; 95% CI, 0.60 to 0.85; P < .003), as was OS (HR, 0.79; 95% CI, 0.63 to 0.99; P = .048), than on conventional chemotherapy (TAC × 6). DFS was longer after response-guided chemotherapy in all hormone receptor–positive tumors (luminal A HR = 0.55, luminal B [human epidermal growth factor receptor 2 (HER2) negative] HR = 0.40, and luminal B [HER2 positive] HR = 0.56), but not in hormone receptor–negative tumors (HER2 positive [nonluminal] HR = 1.01 and triple negative HR = 0.87). Pathologic complete response did not predict these survival effects. pCR predicted an improved DFS in triple-negative (HR = 6.67), HER2-positive (nonluminal; HR 5.24), or luminal B (HER2-negative) tumors (HR = 3.74). Conclusion This exploratory analysis suggests that response-guided neoadjuvant chemotherapy might improve survival and is most effective in hormone receptor–positive tumors. If confirmed, the response-guided approach could provide a clinically meaningful advantage for the neoadjuvant over the adjuvant approach in early breast cancer.

Frequency of TLE3 overexpression in breast carcinoma subtypes including a large cohort of triple-negative patients.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 1040-1040
Author(s):  
Gargi D. Basu ◽  
Anatole Ghazalpour ◽  
David Arguello ◽  
Raheela Ashfaq ◽  
Zoran Gatalica ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Hormone Receptor ◽  
Triple Negative ◽  
Metastatic Breast ◽  
Large Cohort ◽  
Breast Cancer Patients ◽  
Her2 Positive ◽  
Hormone Receptor Positive ◽  
Triple Negative Subtype

1040 Background: The taxanes are an important class of agents for the treatment of a broad range of malignancies including breast cancer. They improve survival in patients with early stage and metastatic breast cancer. Transducin-like enhancer of split 3 (TLE3) is a transcriptional repressor which influences growth and microtubule stability and its expression has been implicated in response to taxane therapy in breast cancer. We investigated the tumor expression of TLE3 in breast cancer patients, including a large cohort of the triple negative subtype. Methods: We analyzed TLE3 (M-201), ER(1D5), PR(PgR636) and HER2/neu(Polyclonal) expression by immunohistochemistry in 978 breast cancer patients. Immunoreactivity was assessed by scoring the percentage of cells stained in each field and by the intensity of staining. Results: To sub-classify the 978 breast cancer patients, we utilized hormone receptors (ER and PR) and HER2 expression/amplification. Overall, 36% of the total breast cancer patients were hormone receptor positive, 15% were HER2 positive and 49% were triple negative. The percentage of triple negative patients was higher in our cohort, given the fact that molecular profiling services are used more frequently for this subtype. A total of 477 patients were triple negative of which 61% stained positive for TLE3 expression. Of the 150 HER2 positive patients, 73% stained positive for TLE3 expression as compared with 82% TLE3 positivity in the 351 hormone receptor positive patients. By pairwise comparison, the hormone receptor positive vs triple-negative subtype showed the highest statistical significance in ratios of TLE3 positives (p =2.5e-10). Conclusions: Our results show that TLE3 is over-expressed in the majority of HER2 positive and hormone receptor positive breast cancer patients. Interestingly, the frequency of over-expression of TLE3 was lowest in the triple negative subtype thereby making it more important to identify those patients in this group who are most likely to respond to taxanes prior to therapy. To our knowledge, this is the first study providing a comprehensive review of TLE expression in breast cancer subtypes.

scholarly journals Identification of p53 and Its Isoforms in Human Breast Carcinoma Cells

2014 ◽  
Vol 2014 ◽  
pp. 1-10 ◽  
Author(s):  
Zorka Milićević ◽  
Vladan Bajić ◽  
Lada Živković ◽  
Jelena Kasapović ◽  
Uroš Andjelković ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Breast Carcinoma ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Genetic Alterations ◽  
Carcinoma Cells ◽  
Nuclear Fraction ◽  
Nuclear Staining ◽  
Human Breast ◽  
Breast Carcinoma Cells

In breast carcinoma, disruption of the p53 pathway is one of the most common genetic alterations. The observation that the p53 can express multiple protein isoforms adds a novel level of complexity to the outcome of p53 mutations. p53 expression was analysed by Western immunoblotting and immunohistochemistry using monoclonal antibodies DO-7, Pab240, and polyclonal antiserum CM-1. The more frequently p53-positive nuclear staining has been found in the invasive breast tumors. One of the most intriguing findings is that mutant p53 appears as discrete dot-shaped regions within the nucleus of breast cancer cells. In many malignant cells, the nucleolar sequestration of p53 is evident. These observations support the view that the nucleolus is involved directly in the mediation of p53 function or indirectly by the control of the localization of p53 interplayers. p53 expressed in the nuclear fraction of breast cancer cells revealed a wide spectrum of isoforms. p53 isoforms ΔNp53 (47 kDa) and Δ133p53β(35 kDa), known as dominant-negative repressors of p53 function, were detected as the most predominant variants in nuclei of invasive breast carcinoma cells. The isoforms expressed also varied between individual tumors, indicating potential roles of these p53 variants in human breast cancer.

scholarly journals Subtype of Breast Cancer in Lao People’s Democratic Republic: A Study in a Limited-Resource Setting

2018 ◽  
Vol 4 (Supplement 3) ◽  
pp. 23s-23s
Author(s):  
Thitsamay Luangxay ◽  
Siriphone Virachith
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Progesterone Receptor ◽  
Hormone Receptor ◽  
Triple Negative ◽  
Democratic Republic ◽  
Her2 Positive ◽  
Lao People’S Democratic Republic ◽  
Lao People's Democratic Republic ◽  
Hormone Receptor Positive

Purpose Three main treatment markers—estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2) —are not routinely tested as a result of a lack of infrastructure of health care facilities. Quality control with which to validate these tests is also not available, and patients or their families have to pay for additional examination cost. Without hormonal receptor and HER2 status, treatment decisions are based on clinical finding; therefore, it is almost impossible to select patients who will benefit from therapy. Currently, none of the related research has ever been published in Lao People’s Democratic Republic. Methods From 2013 to 2016, formalin-fixed, paraffin embedded tissue blocks of 76 patients with primary breast cancer were retrieved at the University of Health Sciences (Vientiane, Lao People’s Democratic Republic). Patient information and previous histologic reports were reviewed. Immunohistochemistry was performed using antibodies against estrogen receptor, progesterone receptor, HER2/neu, and the protein encoded by the MKI67 gene (MIB-I). Results Mean age of patients was 49 years, with a majority of histologic type of invasive ductal carcinoma, not otherwise specified (90.7%). Proportions of each subtype were as follows: hormone receptor positive and HER2 negative, 44.7%; hormone receptor positive and HER2 positive, 3.9%; hormone receptor negative and HER2 positive,13.2%; and triple negative, 38.2%. Of patients, 40.8% were estrogen receptor positive and 47.4% were progesterone receptor positive. More than one half had poorly differentiated cancer (65.8%), followed by moderately differentiated cancer (34.2%). Tumors presented with pT2 (60.5%), followed by pT3 (25.0%) and pT4 (7.9%). Conclusion Breast cancer among Lao women is characterized by a large percentage of the triple-negative subtype as well as by being less susceptible to hormonal receptors. Most of our patients presented with locally advanced stage. HER2-positive and triple-negative breast cancer must be further investigated. To provide adequate care, basic pathology services should be the first requirement in Lao People’s Democratic Republic. Our findings could provide fundamental, useful data for a national policy to control breast cancer in the future. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc . No COIs from the authors.

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