scholarly journals High-throughput allelic expression imbalance analyses identify candidate breast cancer risk genes

2019 ◽  
Author(s):  
Mahdi Moradi Marjaneh ◽  
Haran Sivakumaran ◽  
Kristine M Hillman ◽  
Susanne Kaufmann ◽  
Nehal Hussein ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Regulatory Elements ◽  
Normal Breast ◽  
Allelic Expression ◽  
Allelic Expression Imbalance ◽  
Risk Genes ◽  
Causal Variants ◽  
Breast Cells

ABSTRACTFine-mapping of breast cancer GWAS regions has identified 195 high confidence signals containing more than 5,000 credible causal variants (CCVs). The CCVs are predominantly noncoding and enriched in regulatory elements and thus may confer the risk by altering gene expression in cis. We analyzed allelic expression imbalance (AEI) of genes surrounding known breast cancer signals, using normal breast and breast tumor transcriptome data and imputed genotypes. Fourteen genes, including NTN4, were identified whose expression was associated with CCV genotype. We showed that CCVs at this signal were located within an enhancer that physically interacts with the NTN4 promoter. Furthermore, knockdown of NTN4 in breast cells increased cell proliferation in vitro and tumor growth in vivo. Here, we present the most comprehensive AEI analysis of breast cancer CCVs resulting in identification of new candidate risk genes.

scholarly journals Suppression of MD2 inhibits breast cancer in vitro and in vivo

2021 ◽  
Author(s):  
S. Zheng ◽  
W. Fu ◽  
R. Ma ◽  
Q. Huang ◽  
J. Gu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Breast Carcinoma ◽  
Normal Breast ◽  
Migration And Invasion ◽  
Dependent Manner ◽  
Breast Cells ◽  
4T1 Cells ◽  
Mcf 7

Abstract Purpose To explore the effects of the intervening measure targeting myeloid differentiation 2 (MD2) on breast cancer progression in vitro and in vivo. Methods The expression of MD2 in normal breast cells (Hs 578Bst) and three kinds of breast carcinoma cell lines (MCF-7, MDA-MB-231 s and 4T1) were detected by western blot. MTT assay was used to detect the proliferation of 4T1 cells treated by L6H21, cell migration and invasion was measured by wound healing assay and trans-well matrigel invasion assay, respectively. In addition, to further study the role of MD2 in tumor progression, we assessed the effects of inhibition of MD2 on the progression of xenograft tumors in vivo. Results The expression of MD2 is much higher in MDA-MB-231 s and 4T1cells than that in normal breast cells (Hs 578Bst) or MCF-7 cells (p < 0.05). In vitro, suppression of MD2 by L6H21 has a significant inhibition of proliferation, migration and invasion in 4T1 cells in dose-dependent manner. In vivo, L6H21 pretreatment significantly improved survival of 4T1-bearing mice (p < 0.05). Additionally, we also observed that none of the mice died from the toxic effect of 10 mg kg−1 L6H21 in 60 days. Conclusion Overall, this work indicates that suppression of MD2 shows progression inhibition in vitro and significantly prolong survival in vivo. These findings provide the potential experimental evidence for using MD2 as a therapeutic target of breast carcinoma.

scholarly journals Suppression of MD2 Inhibits Breast Cancer in Vitro and in Vivo

2021 ◽  
Author(s):  
Shurong Zheng ◽  
Weida Fu ◽  
Ruimin Ma ◽  
Qidi Huang ◽  
Junwei Gu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Breast Carcinoma ◽  
Normal Breast ◽  
Migration And Invasion ◽  
Dependent Manner ◽  
Breast Cells ◽  
4T1 Cells ◽  
Mcf 7

Abstract Background: To explore the effects of the intervening measure targeting myeloid differentiation 2 (MD2) on breast cancer progression in vitro and in vivo. Methods: The expression of MD2 in normal breast cells (Hs 578Bst) and three kinds of breast carcinoma cell lines (MCF-7, MDA-MB-231s and 4T1) were detected by western blot. MTT assay was used to detect the proliferation of 4T1 cells treated by L6H21, cell migration and invasion was measured by wound healing assay and transwell matrigel invasion assay, respectively. In addition, to further study the role of MD2 in tumor progression, we assessed the effects of inhibition of MD2 on the progression of xenograft tumors in vivo.Results: The expression of MD2 is much higher in MDA-MB-231s and 4T1cells than that in normal breast cells (Hs 578Bst) or MCF-7 cells (P <0.05). In vitro, suppression of MD2 by L6H21 has a significant inhibition of proliferation, migration and invasion in 4T1 cells in dose-dependent manner. In vivo, L6H21 pretreatment significanly improved survival of 4T1-bearing mice (P <0.05). Additionally, we also observed that there was none of the mice died from the toxic of 10 mg·kg−1 L6H21 in 60 days. Conclusion: Overall, this work indicates that suppression of MD2 shows progression inhibition in vitro and significantly prolong survival in vivo. These findings provide the potential experimental evidence for using MD2 as a therapeutic target of breast carcinoma.

Effects of Sambucus Ebulus Extract on Cell Proliferation and Viability of Triple-Negative Breast Cancer: An In Vitro and In Vivo Study

2021 ◽  
Vol 21 ◽  
Author(s):  
Vahid F. Omrani ◽  
Ameneh Koochaki ◽  
Sahar Behzad ◽  
Vahid Kia ◽  
Peyman Ghasemi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Cell Cycle ◽  
Cell Proliferation ◽  
Triple Negative ◽  
Normal Breast ◽  
Sambucus Ebulus ◽  
Breast Cells

Background: Triple-negative breast cancer (TNBC) accounts for 15% of all breast cancer (BC) cases and is a severe type of BC. Since medicinal herbs containing biocompatible substances that are accepted by patient more than chemical therapeutics, they can be considered a safe option for treating BC. Objective: This study evaluated the effect of Sambucus Ebulus (S. ebulus) extract on a model of TNBC. Methods: S. ebulus extract was prepared using petroleum ether, ethyl acetate, and methanol. The petroleum ether extract was fractionated and analyzed using vacuum liquid chromatography and GC-MS, respectively. MDA-MB-231 and MCF-10A were used as TNBC and normal breast cells, respectively. Flowcytometry and MTT assays were performed to evaluate cell cycle, apoptosis, and viability of the cells. Gene expression analysis was performed using RT-qPCR. Nude mouse allograft tumor models were used, and pathological sections were evaluated. Results: The findings indicated that S. ebulus extract remarkably decreased cell proliferation and viability. The extract had no toxicity to the normal breast cells but efficiently killed the cancer cells. Cell cycle- and apoptosis-related gene expression showed that fraction 4 of S. ebulus extract significantly increased the expression of Bax, Bak, P53, and c-MYC. Conclusion: This study showed satisfactory results of the effect of S. ebulus extract on clearing BC cells both in vitro and in vivo. Thus, S. ebulus extract may be a safe herbal compound for eliminating BC cells without toxicity to host cells.

scholarly journals Prolyl hydroxylase substrate adenylosuccinate lyase is an oncogenic driver in triple negative breast cancer

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Giada Zurlo ◽  
Xijuan Liu ◽  
Mamoru Takada ◽  
Cheng Fan ◽  
Jeremy M. Simon ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Protein Level ◽  
Triple Negative ◽  
Normal Breast ◽  
Cancer Subtypes ◽  
Adenylosuccinate Lyase ◽  
Non Coding Rna

AbstractProtein hydroxylation affects protein stability, activity, and interactome, therefore contributing to various diseases including cancers. However, the transiency of the hydroxylation reaction hinders the identification of hydroxylase substrates. By developing an enzyme-substrate trapping strategy coupled with TAP-TAG or orthogonal GST- purification followed by mass spectrometry, we identify adenylosuccinate lyase (ADSL) as an EglN2 hydroxylase substrate in triple negative breast cancer (TNBC). ADSL expression is higher in TNBC than other breast cancer subtypes or normal breast tissues. ADSL knockout impairs TNBC cell proliferation and invasiveness in vitro and in vivo. An integrated transcriptomics and metabolomics analysis reveals that ADSL activates the oncogenic cMYC pathway by regulating cMYC protein level via a mechanism requiring ADSL proline 24 hydroxylation. Hydroxylation-proficient ADSL, by affecting adenosine levels, represses the expression of the long non-coding RNA MIR22HG, thus upregulating cMYC protein level. Our findings highlight the role of ADSL hydroxylation in controlling cMYC and TNBC tumorigenesis.

scholarly journals The normal breast microenvironment of premenopausal women differentially influences the behavior of breast cancer cells in vitro and in vivo

BMC Medicine ◽  
2010 ◽  
Vol 8 (1) ◽  
Author(s):  
Jodie M Fleming ◽  
Tyler C Miller ◽  
Mariam Quinones ◽  
Zhen Xiao ◽  
Xia Xu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Premenopausal Women ◽  
Normal Breast

scholarly journals Intracellular and Extracellular MicroRNAs in Breast Cancer

2011 ◽  
Vol 57 (1) ◽  
pp. 18-32 ◽  
Author(s):  
Claire Corcoran ◽  
Anne M Friel ◽  
Michael J Duffy ◽  
John Crown ◽  
Lorraine O'Driscoll
Keyword(s):  
Breast Cancer ◽  
Therapeutic Targets ◽  
Systemic Circulation ◽  
Normal Breast ◽  
Response To Treatment ◽  
In Vivo Models ◽  
Diagnosis And Prognosis ◽  
Extracellular Mirnas

BACKGROUND Successful treatment of breast cancer is enhanced by early detection and, if possible, subsequent patient-tailored therapy. Toward this goal, it is essential to identify and understand the most relevant panels of biomarkers, some of which may also have relevance as therapeutic targets. METHODS We critically reviewed published literature on microRNAs (miRNAs) as relevant to breast cancer. SUMMARY Since the initial recognition of the association of miRNAs with breast cancer in 2005, studies involving cell lines, in vivo models, and clinical specimens have implicated several functions for miRNAs, including suppressing oncogenesis and tumors, promoting or inhibiting metastasis, and increasing sensitivity or resistance to chemotherapy and targeted agents in breast cancer. For example, miR-21 is overexpressed in both male and female breast tumors compared with normal breast tissue and has been associated with advanced stage, lymph node positivity, and reduced survival time. miR-21 knock-down in cell-line models has been associated with increased sensitivity to topotecan and taxol in vitro and the limitation of lung metastasis in vivo. Furthermore, the discovery of extracellular miRNAs (including miR-21), existing either freely or in exosomes in the systemic circulation, has led to the possibility that such molecules may serve as biomarkers for ongoing patient monitoring. Although additional investigations are necessary to fully exploit the use of miRNAs in breast cancer, there is increasing evidence that miRNAs have potential not only to facilitate the determination of diagnosis and prognosis and the prediction of response to treatment, but also to act as therapeutic targets and replacement therapies.

scholarly journals TGF-β1 stimulates epithelial–mesenchymal transition and cancer-associated myoepithelial cell during the progression from in situ to invasive breast cancer

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Li Wang ◽  
Cong Xu ◽  
Xia Liu ◽  
Yang Yang ◽  
Lu Cao ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Invasive Breast Cancer ◽  
Ductal Carcinoma ◽  
Myoepithelial Cells ◽  
Normal Breast ◽  
Emt Markers ◽  
Tgf Β1

Abstract Background The progression of ductal carcinoma in situ (DCIS) into invasive ductal carcinoma (IDC) is prevented by normal breast myoepithelial cells. Studies have suggested that EMT-associated genes were enriched in IDC in contrast to DCIS. This paper explored the relationship and potential mechanism between myoepithelial cells and EMT-associated genes in facilitating the transformation from DCIS to breast cancer. Methods EMT markers and myoepithelial phenotypic markers in IDC, DCIS, and healthy breast tissue were characterized using immunohistochemical assay. Both in vivo and in vitro models were created to mimic the various cell–cell interactions in the development of invasive breast cancer. Results We found that EMT markers were more abundant in invasive carcinomas than DCIS and adjacent normal breast tissue. Meanwhile, TGF-β1 regulated the morphology of MCF-7 (epithelial cells substitute) migration and EMT markers during the transformation from DCIS to invasive breast cancer. Additionally, TGF-β1 also regulated invasion, migration and cytokines secretion of MDA-MB-231 (myoepithelial cells substitute) and epithelial cells when co-cultured with MCF-7 both in vitro and in vivo. Conclusions In conclusion, these findings demonstrated that both EMT phenotypes and cancer-associated myoepithelial cells may have an impact on the development of invasive breast cancer.

scholarly journals Long noncoding RNA FGF14-AS2 inhibits breast cancer metastasis by regulating the miR-370-3p/FGF14 axis

2020 ◽  
Vol 6 (1) ◽  
Author(s):  
Yucui Jin ◽  
Ming Zhang ◽  
Rui Duan ◽  
Jiashu Yang ◽  
Ying Yang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Noncoding Rna ◽  
Cancer Metastasis ◽  
Clinical Stage ◽  
Breast Cancer Metastasis ◽  
Normal Breast ◽  
Advanced Clinical Stage ◽  
Cancer Tissues

Abstract Long noncoding RNAs (lncRNAs) have emerged as important regulators in cancers, including breast cancer. However, the overall biological roles and clinical significance of most lncRNAs are not fully understood. This study aimed to elucidate the potential role of a novel lncRNA FGF14-AS2 and the mechanisms underlying metastasis in breast cancer. The lncRNA FGF14-AS2 was significantly downregulated in breast cancer tissues; patients with lower FGF14-AS2 expression had advanced clinical stage. In vitro and in vivo assays of FGF14-AS2 alterations revealed a complex integrated phenotype affecting breast cancer cell migration, invasion, and tumor metastasis. Mechanistically, FGF14-AS2 functioned as a competing endogenous RNA of miR-370-3p, thereby leading to the activation of its coding counterpart, FGF14. Clinically, we observed increased miR-370-3p expression in breast cancer tissues, whereas FGF14 expression was decreased in breast cancer tissues compared to the adjacent normal breast tissues. FGF14-AS2 expression was significantly negatively correlated with miR-370-3p expression, and correlated positively to FGF14 expression. Collectively, our findings support a model in which the FGF14-AS2/miR-370-3p/FGF14 axis is a critical regulator in breast cancer metastasis, suggesting a new therapeutic direction in breast cancer.

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