Aggressiveness Of Breast Carcinoma Research Articles

Role of Estrogen Receptor Alpha rs3798577 Polymorphism in Breast Carcinoma Risk Determination

BACKGROUND: Interaction between estrogen and estrogen receptor (ER) takes part in the regulation and differentiation of breast tumorigenesis. Some ERα polymorphisms, including ERα rs3798577, are reported to be associated with the risk and aggressiveness of breast carcinoma since the site was reported to be targeted by microRNA, which can further modulate the ERα expression. Hence, this study was conducted to disclose the possible role of ERα SNP rs3798577 on breast carcinoma patients.METHODS: Samples were taken from the post-mastectomy breast carcinoma tissues of female patients and screened based on the completeness of medical and histopathological records. DNA isolation was proceeded using real time-polymerase chain reaction (RT-PCR) then analyzed for high resolution melting (HRM). The nucleotide base sequence was then analyzed based on rs3798577 ERα polymorphism. ER immunohistochemistry test was carried out and counted quantitatively based on the staining intensity and the percentage of the stained cells.RESULTS: Out of 65 samples, there were 33 samples as wild type and 32 samples as variant type. Most variant and wild type had >80% ERα percentage. Most variant type had middle ERα intensity, while wild type had strong ERα intensity. Higher percentage of variant type (52.2%) was found with weak ERα histoscore, meanwhile higher percentage of wild type (52.4%) was found with strong ERα histoscore, but not significant (p=0.725).CONCLUSION: ERα rs3798577 variant type had a lower ERα intensity and weaker ERα histoscore compared to the wild type, suggesting that ERα rs3798577 polymorphism might play a role in breast carcinoma risk determination.KEYWORDS: breast cancer, ERα, rs3798577, polymorphism, immunoexpression

Aggressiveness of Breast Carcinoma in Young Pre-Menopausal Patients

Background: Breast cancer is the most commonly diagnosed malignancy in female population. Aim: To determine and compare the frequency of aggressiveness of breast cancer in pre and post-menopausal patients. Study design: Cross sectional study Place and duration of Study: Department of Histopathology, K.E. Medical University Lahore from 1st January 2016 to 31st December 2018. Methodology: One hundred and fifty female patients diagnosed with breast cancer to assess the aggressiveness of breast cancer in young - premenopausal patients. Post-Surgical Modified Radical Mastectomy specimens were submitted and evaluated for grade, stage, involved lymph nodes, tumor size and metastasis. Results: Sixty four percent of the tumors were left sided and the invasive ductal carcinoma was the most dominant histologic type (96%). Ninety two patients were premenopausal while 58 were post-menopausal. Nodal positivity in patients less than 40 years was more pronounced (74.2% versus 56.8%, p=0.029). Conclusion: Young premenopausal patients represent high risk group for advanced breast cancer. Key words: Breast Cancer, Young, Premenopausal, Post-menopausal, Invasive Ductal Carcinoma

Tripartite motif containing 28 (TRIM28) promotes breast cancer metastasis by stabilizing TWIST1 protein.

TRIM28 regulates its target genes at both transcriptional and posttranscriptional levels. Here we report that a TRIM28-TWIST1-EMT axis exists in breast cancer cells and TRIM28 promotes breast cancer metastasis by stabilizing TWIST1 and subsequently enhancing EMT. We find that TRIM28 is highly expressed in both cancer cell lines and advanced breast cancer tissues, and the levels of TRIM28 and TWIST1 are positively correlated with the aggressiveness of breast carcinomas. Overexpression and depletion of TRIM28 up- and down-regulates the protein, but not the mRNA levels of TWIST1, respectively, suggesting that TRIM28 upregulates TWIST1 post-transcriptionally. Overexpression of TRIM28 in breast cancer cell line promotes cell migration and invasion. Knockdown of TRIM28 reduces the protein level of TWIST1 with concurrent upregulation of E-cadherin and downregulation of N-cadherin and consequently inhibits cell migration and invasion. Furthermore, Immunoprecipitation and GST pull-down assays demonstrated that TRIM28 interacts with TWIST1 directly and this interaction is presumed to protect TWIST1 from degradation. Our study revealed a novel mechanism in breast cancer cells that TRIM28 enhances metastasis by stabilizing TWIST1, suggesting that targeting TRIM28 could be an efficacious strategy in breast cancer treatment.

Abstract P4-06-03: TMEPAI a Novel Prognostic Marker for TGF-β Dependency of Metastatic Breast Cancers: Converts Tumor Suppressive TGF-β into a Tumor Promoter

Abstract Background: The dependency of many aggressive and treatment resistant breast cancers on transforming growth factor-beta (TGF-β) for their growth and invasiveness is paradoxical because TGF-β is a classical tumor suppressor that inhibits the growth of normal and early neoplastic breast epithelium. Therefore, we addressed the question how does TGF-β signaling transform from its expected role as a tumor suppressor in early cancer to that of a tumor promoter that facilitates growth and invasion in the late stages? Materials and methods: TMEPAI RNA was quantitated by for qPCR with SYBR green in an Applied Biosystems 7500 Real Time PCR System. pLKO. 1 based lentiviral vector was used to knockdown TMEPAI. Immunoblotting, invasion assays and tumor xenografts were performed using standard methods. Results: TMEPAI expression is observed in ER/PR-negative and HER2-negative breast tumors compared to their matched normal/benign tissues. TMEPAI protein was found to be highly expressed in aggressive and invasive breast cancer cells compared to non-invasive ER-positive and HER2-negative breast cancer cells. Importantly, TGF-β induced late growth spurt in MDA-MB-231 cells and inhibited cell growth in normal mammary epithelial cells (HME). While TGF-β stimulated TMEPAI RNA by ∼40 fold and protein by ∼8-10 fold in MDA-MB-231 cells, it had minimal effect on HME. Both basal expression and TGF-β induction of TMEPAI were completely abolished by SB431542, a pharmacological inhibitor of TGF-β signaling as well as by overexpression of Smad7 or dominant negative TGF-β RI (DN Alk-5). We confirmed TMEPAI as a direct target gene of TGF-β signaling when breast cancer cells MDA-MB-468 and MCF-7 that do not express TMEPAI and are defective in either Smad4 or TGF-β receptor I respectively, by exogenously expressing Smad4 in MDA-MB-468 and Alk-5 in MCF-7 to restore TMEPAI induction by TGF-β. Notably, knockdown of TMEPAI has profound corrective effects on cancer cell growth in vitro and in vivo. These important biological effects were accompanied by increase of cellular levels of the tumor suppressor PTEN and p27kip1, decreased activation of the PI3K signaling mediator Akt, and diminished expression of the oncogenic proteins Hif-1a, and VEGF. Discussion: Our results indicate that increase of TMEPAI protein — further exacerbated by TGF-β — may play a crucial role in TGF-β mediated tumor promotion. We believe that increased expression of TMEPAI by genomic amplification and/or epigenetic events contributes to the cancer phenotype and oncogenic progression through regulation of critical proteins involved in growth, epithelial mesenchymal transition (EMT), and angiogenesis, thereby increasing the aggressiveness of breast carcinomas. Thus, increase of TMEPAI and its induction by TGF-β to pathological levels may be the key lynchpin that explains the conversion of tumor suppressive TGF-β into a tumor promoter and TGF-β dependent cancer cell aggressiveness. Moreover, the data suggest that TMEPAI might serve as a novel prognostic marker for aggressiveness, invasiveness and TGF-β dependency of metastatic breast cancers. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-06-03.