FBP1 modulates cell metabolism of breast cancer cells by inhibiting the expression of HIF-1α.

This study aimed to investigate the function of fructose-1, 6-bisphosphatase 1 (FBP1) in regulating cell growth and metabolism through hypoxia-inducible factor 1α (HIF-1α)-dependent hypoxic response in breast cancer cells. Two human breast carcinoma cell lines, including luminal-like cell line MCF-7 and basal-like cell line MDA-MB-468, were cultured under hypoxia condition, then the expressions of FBP1 and HIF-1α were detected by western blotting. In addition, up-regulated FPB1 in MDA-MB-468 cells were induced by lentivirus. Next, cell growth, migration and glucose metabolism were evaluated by MTT assay, Transwell and commercial kits, as well as the expressions of HIF-1α target genes, including pyruvate dehydrogenase kinase 1 (PDK1), lactate dehydrogenase A (LDHA), glucose transporter 1 (GLUT1) and vascular endothelial growth factor (VEGF) were detected by RT-qPCR. Furthermore, chromatin immunoprecipitation was used to estimate whether the hypoxia response elements (HREs) of PDK1, LDHA, GLUT1 and VEGF promoters were incorporated with FBP1. FBP1 was downregulated in MDA-MB-468 cells compared with MCF-7 cells. Overexpression of FBP1 in MDA-MB-468 cells reduced cell growth (p < 0.05) and migration (p < 0.05) as well as glycose consumption (p < 0.05) and lactate production (p < 0.05). In addition, overexpressed FBP1 inhibited HIF-1α protein expression and the mRNA levels of PDK1, LDHA, GLUT1 and VEGF (p < 0.05) under hypoxia condition. Also, FBP1 was revealed to have a concrete connection with PDK1. This study reveal that overexpressed FBP1 may repress tumor growth, migration and glycolysis via targeting HIF-1α in BLBC.

Overexpression of Raf-1 in basal-like carcinoma of the breast: correlation with clinicopathology and prognosis.

AIM OF THE STUDY: Increased Raf-1 expression has been associated with an aggressive behaviour in some carcinomas such as pulmonary carcinoma and renal carcinoma. However, its role in breast cancer, especially in basal-like carcinoma of the breast (BLBC), has not been defined. MATERIAL AND METHODS: The current study attempted to investigate the expression pattern of Raf-1 protein in BLBC, in relation to the biological behaviour and prognosis of the carcinoma. Expression of Raf-1 was detected by immunohistochemistry in carcinoma specimens from 74 cases of BLBC, and associations between their expression and the clinicopathological characteristics were statistically assessed. RESULTS: The patients' age, tumour size, BRCA1, and p53 protein expression was not significantly different between the Raf-1-positive and Raf-1-negative expression groups (p > 0.05). The proportion of histological grade 3 tumours was not significantly higher in the Raf-1 positive group than that of grade 2 tumours (p > 0.05). However, positive cytoplasmic Raf-1 expression was positively correlated to Ki-67 expression (p < 0.05). Also, increased Raf-1 protein was found to exert an unfavourable impact on patients' axillary lymph node metastasis and overall survival (p < 0.05). CONCLUSIONS: The study implies that positive Raf-1 expression in BLBC is associated with a more aggressive phenotype and could be considered as a new prognostic biomarker for poor survival in BLBC patients.

Molecular Classification of Breast Cancer.

Breast carcinomas classified based on traditional morphologic assessment provide useful prognostic information. Although morphology is still the gold standard of classification, recent advances in molecular technologies have enabled the classification of these tumors into four distinct subtypes based on its intrinsic molecular profile that provide both predictive and prognostic information. This article describes the association between the different molecular subtypes with the histologic subtypes of breast cancer and illustrates how these subtypes may affect the appearance of tumors on imaging studies.

circ_NOTCH3 Functions as a Protooncogene Competing With miR-205-5p, Modulating KLF12 Expression and Promoting the Development and Progression of Basal-Like Breast Carcinoma.

Breast cancer is the most common type of cancer diagnosed among women, and basal-like breast carcinoma (BLBC) has been associated with a more aggressive histology, poorer prognosis, and non-responsiveness to hormone therapy. In the present study, the role and molecular mechanism of circular (circ)_NOTCH3 in the development and progression for BLBC was identified. circ_RNAs array was used to screen the ectopic expression of hsa_circ_0109177 (circ_NOTCH3) in BLBC. RT-qPCR was conducted to evaluate the circ_NOTCH3 expression in BLBC tissues and paired normal tissues, as well as related cell lines. Cell function changes were analyzed following circ_NOTCH3 or micro (mi)RNA overexpression or co-expression. Bioinformatics analysis and dual-luciferase reporter assay were performed to predict and verify the binding sites between circ_NOTCH3 and miRNAs. Gene expression changes were assessed using western blotting. circ_NOTCH3 had a significantly higher expression in BLBC tissues and cell lines. The upregulation of circ_NOTCH3 promoted the proliferation, migration, invasion and inhibited the apoptosis for BLBC cells. The opposite results were observed following miR-205-5p overexpression. However, the co-expression of circ_NOTCH3 and miR-205-5p resulted in those restoration. circ_NOTCH3 is capable of binding to miR-205-5p, and upregulating its target gene KLF12, which can be downregulated by miR-205-5p overexpression and restored by the co-expression of circ_NOTCH3 and miR205-5p. circ_NOTCH3, being an protooncogene and a powerful biomarker, can function as a sponge, compete with miR-205-5p, modulate KLF12 expression, and promote the development and progression of BLBC.

A clinicopathological study of triple-negative breast carcinoma in a patient cohort from a tertiary care center in Sri Lanka.

BACKGROUND: Triple negative breast carcinoma (TNBC) and basal-like breast carcinoma (BLBC) are subtypes of breast carcinoma (BCa) that are associated with poor survival. AIMS: To study the prevalence, clinicopathological profile and survival of TNBC among a Sri Lankan patient cohort and to determine the proportion and predictive histological features of BLBC among TNBCs. STUDY SETTING AND DESIGN: A cohort of 221 women undergoing primary surgery for BCa at a tertiary-care center in Sri Lanka was studied. MATERIALS AND METHODS: Clinicopathological and follow-up information were collected by patient interviews and review of slides and clinical records. Estrogen, progesterone, HER2 receptors, and basal markers (CK5/6, CK14, EGFR, 34ßE12) were evaluated immunohistochemically. STATISTICAL ANALYSIS: Data was analyzed with Chi-square test, multinomial logistic regression, and Cox regression using SPSS20.0. RESULTS: Fifty-three (24%) tumors were triple-negative (95%CI = 18.37%-29.63%). On multivariate analysis, young age (P = 0.002), high Nottingham grade (P = 0.005), moderate to severe tumor necrosis (P = 0.004), absent ductal carcinoma in situ (DCIS) (P = 0.04), reduced vascular density at tumor edge (P = 0.016) and distinct cell margins (P = 0.047) predicted TNBC over luminal subgroups, whereas reduced vascular density (P = 0.004) and low TNM stage (P = 0.011) distinguished TNBC and HER2. BLBC accounted for 45.28% (95%CI 32.66%-58.55%-24/53) of TNBC. The presence of extensive necrosis in TNBC correlated significantly with BLBC (P = 0.03). The survival among the TNBC subgroup did not differ significantly from other subgroups. CONCLUSION: Twenty four percent were TNBCs by immunohistochemical analysis, comparable to studies in the Indian subcontinent, however higher than the West. TNBC status correlated with younger age, high tumor grade, necrosis, absent DCIS, reduced vascular density at tumor edge, and distinct cell margins. The presence of moderate to extensive necrosis in TNBC was predictive of BLBC.

Expression Profiling of Clinical Specimens Supports the Existence of Neural Progenitor-Like Stem Cells in Basal Breast Cancers.

BACKGROUND: We previously characterized in salivary adenoid cystic carcinoma (ACC) a novel population of cancer stem cells (CSCs) marked by coexpression of 2 stemness genes, sex-determining region Y (SRY)-related HMG box-containing factor 10 (SOX10) and CD133. We also reported that in ACC and basal-like breast carcinoma (BBC), a triple-negative breast cancer subtype, expression of SOX10 similarly demarcates a highly conserved gene signature enriched with neural stem cell genes. On the basis of these findings, we hypothesized that BBC might be likewise driven by SOX10-positive (SOX10+)/CD133+ cells with neural stem cell properties. MATERIALS AND METHODS: To validate our hypothesis on clinical data, we used a novel approach to meta-analysis that merges gene expression data from independent breast cancer studies and ranks genes according to statistical significance of their coexpression with the gene of interest. Genes that showed strong association with CD133/PROM1 as well as SOX10 were validated across different platforms and data sets and analyzed for enrichment with genes involved in neurogenesis. RESULTS: We identified in clinical breast cancer data sets a highly conserved SOX10/PROM1 gene signature that contains neural stem cell markers common for Schwann cells, ACC, BBC, and melanoma. Identification of tripartite motif-containing 2 (TRIM2), TRIM29, MPZL2, potassium calcium-activated channel subfamily N member 4 (KCNN4), and V-set domain containing T cell activation inhibitor 1 (VTCN1)/B7 homolog 4 (B7H4) within this signature provides insight into molecular mechanisms of CSC maintenance. CONCLUSION: Our results suggest that BBC is driven by SOX10+/CD133+ cells that express neural stem cell-specific markers and share molecular similarities with CSCs of neural crest origin. Our study provides clinically relevant information on possible drivers of these cells that might facilitate development of CSC-targeting therapies against this cancer distinguished with poor prognosis and resistance to conventional therapies.

Immunohistochemistry for Triple-Negative Breast Cancer.

Triple-negative breast cancers are a heterogeneous group of tumors that are, as yet, not entirely understood. Although triple-negative carcinomas are strictly defined as invasive carcinomas lacking expression of estrogen receptor, progesterone receptor, and HER2, some use the terms triple-negative and basal-like cancer synonymously. It should be noted that these are not entirely equivalent. Nevertheless, it has been shown that a panel of immunohistochemical markers can be used as a surrogate for genomic profiling and thus to identify basal-like breast cancers. We describe the panels of immunohistochemical markers that can be applied and how to interpret these markers herein.

Metastases of basal-like breast invasive ductal carcinoma to the endometrium: A case report and review of the literature.

We present a case of single endometrial metastasis from breast invasive ductal cancer. This case was unique because the immunohistochemical staining was negative for human epidermal growth factor receptor 2/neu and estrogen and progesterone receptors, and positive for cytokeratin 5/6 and epidermal growth factor receptor in the primary and metastatic tumor cells. No gross evidence of tumor was observed in other sites. We identified 12 cases of metastases to the endometrium from breast carcinoma from series and case reports in the literature between 1985 and 2014. This review indicated that hormone receptor-positive invasive lobular breast cancer cells are more likely to metastasize to the endometrium than other cell types in patients over 50 years of age.

The clinicopathologic characterizations and prognosis in pafients of basal-like breast cancer / 中华普通外科杂志

Objective To analyze the clinicopathologic characterizations and patients prognosis of basal-like breast cancer. Methods The clinicopathologic eharacterizations,patient 5 year disease-free survival rate and overall survival rate of 25 basal-like breast cancer patients were compared with 34 CerbB2 overexpressing subtype and 37 ER positive subtype breast cancer patients admitted in our hospital in the same period. Results Patients of basal-like breast cancer accounted for 15.7% of all patients admitted.Compared with CerbB2 over-expressing subtype(29.4%)and ER positive subtype(35.1%),basal-like breast cancer patients were eider with 56.0% being≥50 years old(P＜0.05).Basal-like subtype breast cancer was larger in tumor size than ER positive subtype(P＜0.05),56% of basal-like subtype were of poor-differentiated grade pathologically compared with 18% in CerbB2 overexpression type and 16% in ER positive subtype respectively. Meanwhile, axillary lymph node metastasis was hishbar in CerbB2 overexpressing and ER positive subtype(64.7%,64.9%)than that of basal-like subtype(40.0%).Most visceral metastases were found in basal-like and CerbB2 subtype,but there were more local lymph node and bone metastases in ER positive subtype.Five year overall survoval rate of CerbB2 overexpressing subtype (48.5%)and basal-like subtype breast cancer patients(44.1%)were poorer than that of ER positive subtype(83.8%).respectively;However,there was no difference in 5 year disease-free surviVal rate between the three subtypes(42.7%,40.4%,58.3%,respectively).Conclusions Similar to CerbB2 over-expressing subtype.tlle clinicopathologic characterization and prognosis in basal-like breast cancer are poorer than that in ER positive subtype.