The long non-coding RNA ET-20 mediates EMT by impairing desmosomes in breast cancer cells

The vast majority of breast cancer-associated deaths are due to metastatic spread of cancer cells, a process aided by epithelial-mesenchymal transition (EMT). Mounting evidence has indicated that long non-coding RNAs (lncRNAs) also contribute to tumor progression. We report the identification of 114 novel lncRNAs that change their expression during TGFβ-induced EMT in murine breast cancer cells (referred to as EMT-associated transcripts; ETs). Of these, the ET-20 gene localizes in antisense orientation within the Tenascin C (Tnc) gene locus. Tnc is an extra-cellular matrix protein which is critical for EMT and metastasis formation. Both ET-20 and Tnc are regulated by the EMT master transcription factor Sox4. Notably, ablation of ET-20 lncRNA effectively blocks Tnc expression and with it EMT. Mechanistically, ET-20 interacts with desmosomal proteins, thereby impairing epithelial desmosomes and promoting EMT. A short transcript variant of ET-20 is found upregulated in invasive human breast cancer cell lines where it also promotes EMT. Targeting ET-20 appears a therapeutically attractive lead to restrain EMT and breast cancer metastasis in addition to its potential utility as a biomarker for invasive breast cancer.

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miR-214 inhibits epithelial–mesenchymal transition of breast cancer cells via downregulation of RNF8

Acta Biochimica et Biophysica Sinica ◽

10.1093/abbs/gmz067 ◽

2019 ◽

Vol 51 (8) ◽

pp. 791-798 ◽

Cited By ~ 3

Author(s):

Lu Min ◽

Chuanyang Liu ◽

Jingyu Kuang ◽

Xiaomin Wu ◽

Lingyun Zhu

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Cancer Metastasis ◽

Epithelial Mesenchymal Transition ◽

Breast Cancer Metastasis ◽

Breast Cancer Patients ◽

Mesenchymal Transition ◽

Proliferation And Invasion

Abstract MicroRNAs (miRNAs) are a class of endogenous noncoding genes that regulate gene expression at the posttranscriptional level. In recent decades, miRNAs have been reported to play important roles in tumor growth and metastasis, while some reported functions of a specific miRNA in tumorigenesis are contradictory. In this study, we reevaluated the role of miR-214, which has been reported to serve as an oncogene or anti-oncogene in breast cancer metastasis. We found that miR-214 inhibited breast cancer via targeting RNF8, a newly identified regulator that could promote epithelial–mesenchymal transition (EMT). Specifically, the survival rate of breast cancer patients was positively correlated with miR-214 levels and negatively correlated with RNF8 expression. The overexpression of miR-214 inhibited cell proliferation and invasion of breast cancer, while suppression of miR-214 by chemically modified antagomir enhanced the proliferation and invasion of breast cancer cells. Furthermore, miR-214 could modulate the EMT process via downregulating RNF8. To our knowledge, this is the first report that reveals the role of the miR-214–RNF8 axis in EMT, and our results demonstrate a novel mechanism for miR-214 acting as a tumor suppressor through the regulation of EMT.

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A radiosensitizer, gallotannin-rich extract from Bouea macrophylla seeds, inhibits radiation-induced epithelial-mesenchymal transition in breast cancer cells

BMC Complementary Medicine and Therapies ◽

10.1186/s12906-021-03363-6 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Jiraporn Kantapan ◽

Siwaphon Paksee ◽

Aphidet Duangya ◽

Padchanee Sangthong ◽

Sittiruk Roytrakul ◽

...

Keyword(s):

Breast Cancer ◽

Dna Damage ◽

Cell Death ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Epithelial Mesenchymal Transition ◽

Breast Cancer Cell Lines ◽

Mesenchymal Transition ◽

Mammosphere Formation ◽

Radiation Induced

Abstract Background Radioresistance can pose a significant obstacle to the effective treatment of breast cancers. Epithelial–mesenchymal transition (EMT) is a critical step in the acquisition of stem cell traits and radioresistance. Here, we investigated whether Maprang seed extract (MPSE), a gallotannin-rich extract of seed from Bouea macrophylla Griffith, could inhibit the radiation-induced EMT process and enhance the radiosensitivity of breast cancer cells. Methods Breast cancer cells were pre-treated with MPSE before irradiation (IR), the radiosensitizing activity of MPSE was assessed using the colony formation assay. Radiation-induced EMT and stemness phenotype were identified using breast cancer stem cells (CSCs) marker (CD24−/low/CD44+) and mammosphere formation assay. Cell motility was determined via the wound healing assay and transwell migration. Radiation-induced cell death was assessed via the apoptosis assay and SA-β-galactosidase staining for cellular senescence. CSCs- and EMT-related genes were confirmed by real-time PCR (qPCR) and Western blotting. Results Pre-treated with MPSE before irradiation could reduce the clonogenic activity and enhance radiosensitivity of breast cancer cell lines with sensitization enhancement ratios (SERs) of 2.33 and 1.35 for MCF7 and MDA-MB231cells, respectively. Pretreatment of breast cancer cells followed by IR resulted in an increased level of DNA damage maker (γ-H2A histone family member) and enhanced radiation-induced cell death. Irradiation induced EMT process, which displayed a significant EMT phenotype with a down-regulated epithelial marker E-cadherin and up-regulated mesenchymal marker vimentin in comparison with untreated breast cancer cells. Notably, we observed that pretreatment with MPSE attenuated the radiation-induced EMT process and decrease some stemness-like properties characterized by mammosphere formation and the CSC marker. Furthermore, pretreatment with MPSE attenuated the radiation-induced activation of the pro-survival pathway by decrease the expression of phosphorylation of ERK and AKT and sensitized breast cancer cells to radiation. Conclusion MPSE enhanced the radiosensitivity of breast cancer cells by enhancing IR-induced DNA damage and cell death, and attenuating the IR-induced EMT process and stemness phenotype via targeting survival pathways PI3K/AKT and MAPK in irradiated breast cancer cells. Our findings describe a novel strategy for increasing the efficacy of radiotherapy for breast cancer patients using a safer and low-cost natural product, MPSE.

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The role of protein kinase PAK1 in the regulation of estrogen-independent growth of breast cancer

Biomeditsinskaya Khimiya ◽

10.18097/pbmc20146003322 ◽

2014 ◽

Vol 60 (3) ◽

pp. 322-331 ◽

Cited By ~ 2

Author(s):

E.A. Avilova ◽

O.E. Andreeva ◽

V.A. Shatskaya ◽

M.A. Krasilnikov

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Intracellular Signaling ◽

Breast Cancer Cells ◽

Epithelial Mesenchymal Transition ◽

Breast Cancer Cell Lines ◽

Hormone Resistance ◽

Mesenchymal Transition

The main goal of this work was to study the intracellular signaling pathways responsible for the development of hormone resistance and maintaining the autonomous growth of breast cancer cells. In particular, the role of PAK1 (p21-activated kinase 1), the key mitogenic signaling protein, in the development of cell resistance to estrogens was analyzed. In vitro studies were performed on cultured breast cancer cell lines: estrogen-dependent estrogen receptor (ER)-positive MCF-7 cells and estrogen-resistant ER-negative HBL-100 cells. We found that the resistant HBL-100 cells were characterized by a higher level of PAK1 and demonstrated PAK1 involvement in the maintaining of estrogen-independent cell growth. We have also shown PAK1 ability to up-regulate Snail1, one of the epithelial-mesenchymal transition proteins, and obtained experimental evidence for Snail1 importance in the regulation of cell proliferation. In general, the results obtained in this study demonstrate involvement of PAK1 and Snail1 in the formation of estrogen-independent phenotype of breast cancer cells showing the potential role of both proteins as markers of hormone resistance of breast tumors.

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BRMS1L inhibits bone metastasis of breast cancer cells through epigenetic silence of CXCR4.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e13002 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e13002-e13002

Author(s):

Yinghuan Cen ◽

Chang Gong ◽

Jun Li ◽

Gehao Liang ◽

Zihao Liu ◽

...

Keyword(s):

Breast Cancer ◽

Bone Metastasis ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Cancer Metastasis ◽

Breast Cancer Metastasis ◽

Breast Cancer Cell Lines ◽

Breast Cancer Patients ◽

Qrt Pcr ◽

Metastatic Sites

e13002 Background: We previously demonstrated that BRMS1L (breast cancer metastasis suppressor 1 like) suppresses breast cancer metastasis through HDAC1 recruitment and histone H3K9 deacetylation at the promoter of FZD10, a receptor for Wnt signaling. It is still unclear whether BRMS1L regulates organ-specific metastases, such as bone metastasis, the most prevalent metastatic site of breast cancer. Methods: Examination of the expression of BRMS1L in primary tumors, bone metastatic and other metastatic tissues from breast cancer patients was implemented using qRT-PCR and immunohistochemistry staining. To investigate the mechanism by which BRMS1L drives breast cancer bone metastasis, we tested the mRNA expression by qRT-PCR of a set of potential bone related genes (BRGs) based on PubMed database in MDA-MB-231 cells over expressing BRMS1L and MCF-7 cells knocking-down BRMS1L, and detected the expression of CXCR4 in these established cells by western blot. Transwell assays were performed to assess the migration abilities of breast cancer cells towards osteoblasts. ChIP (Chromatin Immuno-Precipitation) were employed to test the interaction between BRMS1L and CXCR4. Results: At both mRNA and protein levels, the expression of BRMS1L was significantly lower in bone metastatic sites than that in primary cancer tissues and other metastatic sites of breast cancer patients. CXCR4 was screened out in a set of BRGs and negatively correlated with the expression of BRMS1L in breast cancer cell lines. BRMS1L inhibited the migration of breast cancer cells towards osteoblasts through CXCL12/CXCR4 axis. In the presence of TSA treatment, breast cancer cell lines showed an increased expression of CXCR4 in a TSA concentration-dependent manner. In addition, ChIP assays verified that BRMS1L directly bound to the promoter region of CXCR4 and inhibited its transcription through promoter histone deacetylation. Conclusions: BRMS1L mediates the migration abilities of breast cancer cells to bone microenvironment via targeting CXCR4 and contributes to bone metastasis of breast cancer cells. Thus, BRMS1L may be a potential biomarker for predicting bone metastasis in breast cancer.

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Tumor-Associated Macrophages of the M1/ M2 Phenotype are Involved in the Regulation of Malignant Biological Behavior of Breast Cancer Cells Through the EMT Pathway

10.21203/rs.3.rs-1158639/v1 ◽

2021 ◽

Author(s):

zhuo Chen ◽

jing Wu ◽

liang Wang ◽

hua Zhao ◽

jie He

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Poor Prognosis ◽

Breast Cancer Cells ◽

Epithelial Mesenchymal Transition ◽

Tissue Microarrays ◽

Biological Behavior ◽

Breast Cancer Cell Lines ◽

Mesenchymal Transition ◽

The Matrix

Abstract Triple negative breast cancer (TNBC) is the most aggressive subtype of breast cancer. More and more studies have shown that the tumor immune microenvironment (TME) of TNBC is closely related to its poor prognosis and early metastasis. We try to explain how tumor-associate macrophages (TAMs）, an important component of the TME, function in the matrix of TNBC. Therefore, we induced THP-1 cells to become M1-TAMs and M2-TAMs, investigated their influence on breast cancer cells. 82 TNBC paraffin samples were made into tissue microarrays. The expression of macrophages makers were measured by immunohistochemistry. Scratch assay, Transwell assay, CCK-8 cell proliferation assay were performed in the co-culture system of breast cancer cells lines and macrophages to observe the invasion and proliferation ability of breast cancer cell lines. Western Blot (WB) was performed to detect the expression of E-cadherin (CDH1) and N-cadherin (CDH2). M2-TAMs were more numerous than M1-TAMs in the matrix of TNBC cancer nests and associated with poor prognosis. M2-TAMs promoted the invasion, migration and proliferation of TNBC cells. M1-TAMs had inhibitory effects. In MCF-7 cells, WB showed a decrease in CDH1 and an increase in CDH2. In MDA-MB-231 cells and BT549 cells, CDH2 expression was reduced and CDH1 expression was increased. All of the above results were statistically significant, p < 0.001. M2-TAMs were more numerous in TNBC and associated with poor prognosis. M2-TAMs promoted the invasion, migration and proliferation of breast cancer cells. The mechanism may be related to the epithelial-mesenchymal transition (EMT).

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Breast Cancer Metastasis: Role of Tumor Microenvironment and Resident Macropahges

Defence Life Science Journal ◽

10.14429/dlsj.1.10058 ◽

2016 ◽

Vol 1 (1) ◽

pp. 48

Author(s):

Khemraj Singh Baghel ◽

Smrati Bhadauria

Keyword(s):

Breast Cancer ◽

Tumor Microenvironment ◽

Cancer Cells ◽

Cancer Metastasis ◽

Epithelial Mesenchymal Transition ◽

Metastatic Breast ◽

Breast Cancer Metastasis ◽

The Body ◽

Tissue Remodelling ◽

Mesenchymal Transition

Metastatic breast cancer is a stage of breast cancer wherever the disease has spread to distant parts of the body. Onset of metastasis is one of the biggest obstacles to the successful treatment of cancer. The potential of a tumor cell to metastasize profoundly depends on its microenvironment, or “niche” interactions with local components. Macrophages provide tropic support to tumors. Resident macrophages contribute a set of common functions, including their capability to defend against microbial infections, to maintain normal cell turnover and tissue remodelling, and to help repair sites of injury. Macrophages are recruited into the tumor microenvironment where they differentiate to become Tumor-associated-macrophages (TAMs). TAMs are the most abundant subpopulation of tumor-stroma and actively drive cancer cell invasion and metastasis. Cancer metastasis is not solely regulated by the deregulation of metastasis promoting or suppressing genes in cancer cells. Recently the interaction between the stromal cells and cancer cells has been demonstrated to promote cancer metastasis. TAMs can advocate epithelial-mesenchymal transition of cancer cells. Loss of e-cadherin, a major phenomenon of epithelial to mesenchymal transition (EMT), reduces adhesiveness and releases cancer cells to distant (secondary) sites. A positive correlation between tumor progression and the expression of matrix metallo proteinases (MMPs) in tumor tissues has been demonstrated in numerous human and animal studies. The dynamic interactions of cancer-cells with TAMs actively promote invasion-metastasis cascade through intercellular-signalling-networks that need better elucidation.

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Novel strategy in breast cancer therapy: Revealing the bright side of ginsenosides

Current Molecular Pharmacology ◽

10.2174/1874467214666210120153348 ◽

2021 ◽

Vol 14 ◽

Author(s):

Farid Hashemi ◽

Ali Zarrabi ◽

Amirhossein Zabolian ◽

Hossein Saleki ◽

Mahdi Vasheghani Farahani ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Therapy ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Cancer Metastasis ◽

Breast Cancer Metastasis ◽

Breast Cancer Therapy ◽

Triterpenoid Saponins ◽

Mesenchymal Transition ◽

Anti Tumor Activity

Breast cancer is one of the leading causes of death worldwide. Breast cancer cells demonstrate uncontrolled proliferation, and high metastatic capacity. They can obtain resistance to chemotherapy and radiotherapy. This has resulted in troublesome problems in its treatment. Nature as a rich source of plant derived-natural products with anti-tumor activity can be of interest in breast cancer therapy. Ginsenosides are triterpenoid saponins and considered as secondary metabolites exclusively found in Panax species. From immemorial times, ginsenosides have been applied in treatment of various disorders such as diabetes, inflammatory diseases, neurological disorders, and particularly, cancer. In the present review, we highlight anti-tumor activity of ginsenosides against breast cancer cells. Ginsenosides are able to induce apoptosis and cell cycle arrest. They interfere with breast cancer metastasis via inhibiting epithelial-to-mesenchymal transition, matrix metalloproteinase proteins and angiogenesis. Ginsenosides can promote efficacy of chemotherapy via suppressing migration and proliferation. Molecular pathways such as phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt), insulin-like growth factor-1, Wnt, microRNAs and long non-coding RNAs are affected by ginsenosides in suppressing breast cancer malignancy. Consequently, ginsenosides are versatile compounds in breast cancer therapy by suppressing growth, and invasion, as well as promoting their sensitivity to chemotherapy.

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lncRNA APOC1P1-3 promoting anoikis-resistance of breast cancer cells

Cancer Cell International ◽

10.1186/s12935-021-01916-w ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Qi Lu ◽

Li Wang ◽

Yabiao Gao ◽

Ping Zhu ◽

Luying Li ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Cancer Metastasis ◽

Critical Role ◽

Systemic Circulation ◽

Breast Cancer Metastasis ◽

Breast Cancer Cell Lines ◽

Anoikis Resistance ◽

Apoptosis Protein

Abstract Background Anoikis resistance plays a critical role in the tumor metastasis by allowing survival of cancer cells in the systemic circulation. We previously showed that long non-coding RNAs APOC1P1-3 (lncRNA APOC1P1-3) inhibit apoptosis of breast cancer cells. In this study, we explored its role in anoikis resistance. Methods We induced anoikis resistance in two breast cancer cell lines (MCF-7 and MDA-MB-231) under anchorage-independent culture conditions and studied lncRNA APOC1P1-3 effects on apoptosis. Using Dual-Luciferase activity assay, we determined whether it specifically binds to miRNA-188-3P. We further explored its role in lung metastasis by injecting MDA-MB-231 and MDA-MB-231-APOC1P1-3-knock-down cells in female BALB/c nude mice. Results We found that lncRNA APOC1P1-3 suppressed early apoptosis of these cells (demonstrated by gain or loss of their function, respectively) and promoted anoikis resistance via reducing activated- Caspase 3, 8, 9 and PARP. Moreover, it specifically binds to the target miRNA-188-3p acting as a “sponge” to block the inhibition of Bcl-2 (an anti-apoptosis protein). Conclusions Our study supports a theory that lncRNA APOC1P1-3 can promote development of breast cancer metastasis via anoikis resistance by specifically binding to miRNA-188-3p to block the inhibition of Bcl-2.

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The Herbal Formula JI017 Induces ER Stress via Nox4 in Breast Cancer Cells

Antioxidants ◽

10.3390/antiox10121881 ◽

2021 ◽

Vol 10 (12) ◽

pp. 1881

Author(s):

Tae Woo Kim ◽

Seong-Gyu Ko

Keyword(s):

Breast Cancer ◽

Combination Therapy ◽

Er Stress ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Epithelial Mesenchymal Transition ◽

Herbal Extract ◽

Breast Cancer Cell Lines ◽

Mesenchymal Transition ◽

Stress Markers

Chemotherapy is a powerful anti-tumor therapeutic strategy; however, resistance to treatment remains a serious concern. To overcome chemoresistance, combination therapy with anticancer drugs is a potential strategy. We developed a novel herbal extract, JI017, with lower toxicity and lesser side effects. JI017 induced programmed cell death and excessive unfolded protein response through the release of intracellular reactive oxygen species (ROS) and calcium in breast cancer cells. JI017 treatment increased the expression of endoplasmic reticulum (ER) stress markers, including p-PERK, p-eIF2α, ATF4, and CHOP, via the activation of both exosomal GRP78 and cell lysate GRP78. The ROS inhibitors diphenyleneiodonium and N-acetyl cysteine suppressed apoptosis and excessive ER stress by inhibiting Nox4 in JI017-treated breast cancer cells. Furthermore, in paclitaxel-resistant breast cancer cell lines, MCF-7R and MDA-MB-231R, a combination of JI017 and paclitaxel overcame paclitaxel resistance by blocking epithelial-mesenchymal transition (EMT) processes, such as the downregulation of E-cadherin expression and the upregulation of HIF-1α, vimentin, Snail, and Slug expression. These findings suggested that JI017 exerts a powerful anti-cancer effect in breast cancer and a combination therapy of JI017 and paclitaxel may be a potential cancer therapy for paclitaxel resistant breast cancer.

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