scholarly journals MicroRNA-941 regulates the proliferation of breast cancer cells by altering histone H3 Ser 10 phosphorylation

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Sunil Kumar Surapaneni ◽  
Zahid Rafiq Bhat ◽  
Kulbhushan Tikoo
Keyword(s):  
Breast Cancer ◽  
Histone H3 ◽  
Xenograft Model ◽  
Fold Increase ◽  
Positive Control ◽  
Intratumoral Injection ◽  
Breast Cancers ◽  
Mammary Fat Pad ◽  
And Migration ◽  
Cycle Regulation

Abstract Breast cancer including triple negative breast cancer (TNBC) represents an important clinical challenge, as these tumours often develop resistance to conventional chemotherapeutics. MicroRNAs play a crucial role in cell-cycle regulation, differentiation, apoptosis, and migration. Herein, we performed Affymetrix Gene Chip miRNA 4.0 microarray and observed differential regulation of miRNAs (75 upregulated and 199 downregulated) in metastatic MDA-MB-231 cells as compared to immortalized human non-tumorigenic breast epithelial (MCF-10A) cells. MicroRNA-941 was significantly upregulated in MDA-MB-231 cells (almost nine-fold increase) in comparison to MCF-10A cells. Transfection of MiRNA-941 inhibitor significantly decreased the proliferation and migration of MDA-MB-231 cells by altering the expressions of p21, Cyclin D1, PP2B-B1, E-cadherin and MMP-13. Interestingly, we provide first evidence that inhibiting miR-941 prevents cell proliferation and phosphorylation of histone H3 at Ser10 residue. Xenograft model of breast cancer was developed by subcutaneous injection of MDA-MB-231 cells into the mammary fat pad of female athymic nude mice (Crl:NU-Foxn1nu). The tumours were allowed to grow to around 60 mm3, thereafter which we divided the animals into seven groups (n = 5). Notably, intratumoral injection of miR-941 inhibitor significantly abolished the tumour growth in MDA-MB-231 xenograft model. 5-Fluorouracil (10 mg/kg, i.p.) was used as positive control in our study. To the best of our knowledge, we report for the first time that targeting miR-941 improves the sensitivity of MDA-MB-231 cells to 5-fluorouracil. This can be of profound clinical significance, as it provides novel therapeutic approach for treating variety of cancers (overexpressing miRNA-941) in general and breast cancers in particular.

Development of orally bioavailable prodrugs of fulvestrant for the treatment of metastatic/advanced breast cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e13027-e13027
Author(s):  
Parva Purohit ◽  
Pathik Brahmkshatriya ◽  
Vishalgiri Goswami
Keyword(s):  
Breast Cancer ◽  
Oral Delivery ◽  
Tumor Volume ◽  
Estrogen Therapy ◽  
Xenograft Model ◽  
Fold Increase ◽  
Tumor Growth Inhibition ◽  
Pharmacokinetic Studies ◽  
Hormone Receptor Positive ◽  
Mcf 7

e13027 Background: Fulvestrant, a potent, selective estrogen receptor degrader, is a primary drug of choice for treating advanced metastatic hormone receptor-positive breast cancer in postmenopausal women following anti-estrogen therapy. However, the existing therapy limits to inconvenient intramuscular injections due to low solubility, weak permeation, high metabolism, and poor pharmacokinetics profile. Additionally, it takes 30 days to reach maximal steady-state plasma concentration, limiting clinical efficacy. To overcome these issues, we modulated physicochemical properties of fulvestrant, enabling its oral delivery to improve bioavailability. Methods: Structurally diverse pro-moieties were appended on fulvestrant to improve solubility and ADME profile. Thermodynamic solubility, plasma/liver microsomal stability, and Caco-2 permeability studies were performed to identify lead molecules. Pharmacokinetic studies were performed for selected molecules in mice. Antitumor activity of once-daily oral dose of three molecules was evaluated in female nude mice using the MCF-7 xenograft model. The efficacy of lead molecules was compared with subcutaneously administered faslodex in terms of percentage tumor growth inhibition. Results: Several prodrugs of fulvestrant were synthesized and evaluated for their intrinsic properties suitable for increasing bioavailability of fulvestrant. Remarkable improvements (̃500 to 2000-fold increase) were achieved in solubility and permeability. The PoC established an increase in systemic plasma exposure of fulvestrant upon oral administration of prodrugs in mice with enhanced bioavailability (1.5-8.7-fold) as compared to fulvestrant given subcutaneously (Table). Herewith, we report the identification of KSHN001022, KSHN001075, and KSHN001126, the prodrugs of fulvestrant, which showed enhanced efficacy with better tumor volume reduction (̃48-88% regression in tumor volume) as compared to that of fulvestrant (78%) in the estrogen-dependent MCF-7 xenograft model. Conclusions: KSHN001 lead candidates demonstrated significantly higher bioavailability, hence, provides a novel strategy to deliver fulvestrant orally to pursue the potential benefits in patients with advanced metastatic disease.[Table: see text]

scholarly journals Review of: Tamoxifen and TRAIL synergistically induce apoptosis in breast cancer cells

2008 ◽  
Vol 11 (2) ◽  
Author(s):  
Alison J. Butt
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Single Agent ◽  
Xenograft Model ◽  
Estrogen Receptor Α ◽  
Tumor Xenograft ◽  
Breast Cancers ◽  
Induced Apoptosis

Citation of original article:C. Lagadec, E. Adriaenssens, R. A. Toillon, V. Chopin, R. Romon, F. Van Coppenolle, H. Hondermarck, X. Le Bourhis. Oncogene advance online publication, 3 September 2007; doi:10.1038/sj.onc.1210749.Abstract of the original article:Tamoxifen (TAM), is widely used as a single agent in adjuvant treatment of breast cancer. Here, we investigated the effects of TAM in combination with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in estrogen receptor-α (ER-α)-positive and -negative breast cancer cells. We showed that cotreatment with TAM and TRAIL synergistically induced apoptosis regardless of ER-α status. By contrast, cotreatment did not affect the viability of normal breast epithelial cells. Cotreatment with TAM and TRAIL in breast cancer cells decreased the levels of antiapoptotic proteins including FLIPs and Bcl-2, and enhanced the levels of proapoptotic proteins such as FADD, caspase 8, tBid, Bax and caspase 9. Furthermore, cotreatment-induced apoptosis was efficiently reduced by FADD- or Bid-siRNA, indicating the implication of both extrinsic and intrinsic pathways in synergistic apoptosis induction. Importantly, cotreatment totally arrested tumor growth in an ER-α-negative MDA-MB-231 tumor xenograft model. The abrogation of tumor growth correlated with enhanced apoptosis in tumor tissues. Our findings raise the possibility to use TAM in combination with TRAIL for breast cancers, regardless of ER-α status.

scholarly journals Inhibition of Triple-Negative Breast Cancer Cell Aggressiveness by Cathepsin D Blockage: Role of Annexin A1

2019 ◽  
Vol 20 (6) ◽  
pp. 1337 ◽  
Author(s):  
Mariana Zóia ◽  
Fernanda Azevedo ◽  
Lara Vecchi ◽  
Sara Mota ◽  
Vinícius Rodovalho ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cathepsin D ◽  
Triple Negative ◽  
Functional Results ◽  
Annexin A1 ◽  
Breast Cancers ◽  
Invasion And Migration ◽  
And Migration ◽  
Induced Apoptosis ◽  
In Silico Molecular Docking

Triple-negative breast cancers (TNBCs) are more aggressive than other breast cancer (BC) subtypes and lack effective therapeutic options. Unraveling marker events of TNBCs may provide new directions for development of strategies for targeted TNBC therapy. Herein, we reported that Annexin A1 (AnxA1) and Cathepsin D (CatD) are highly expressed in MDA-MB-231 (TNBC lineage), compared to MCF-10A and MCF-7. Since the proposed concept was that CatD has protumorigenic activity associated with its ability to cleave AnxA1 (generating a 35.5 KDa fragment), we investigated this mechanism more deeply using the inhibitor of CatD, Pepstatin A (PepA). Fourier Transform Infrared (FTIR) spectroscopy demonstrated that PepA inhibits CatD activity by occupying its active site; the OH bond from PepA interacts with a CO bond from carboxylic acids of CatD catalytic aspartate dyad, favoring the deprotonation of Asp33 and consequently inhibiting CatD. Treatment of MDA-MB-231 cells with PepA induced apoptosis and autophagy processes while reducing the proliferation, invasion, and migration. Finally, in silico molecular docking demonstrated that the catalytic inhibition comprises Asp231 protonated and Asp33 deprotonated, proving all functional results obtained. Our findings elucidated critical CatD activity in TNBC cell trough AnxA1 cleavage, indicating the inhibition of CatD as a possible strategy for TNBC treatment.

EPO Receptor Overexpression in Breast Cancer Cells Enhances EPO Sensitivity, Induces ERK and AKT Phosphorylation and Promotes Cellular Proliferation and Migration through a JNK-Dependent Pathway.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4083-4083
Author(s):  
Ping Fu ◽  
Xiaohong Jiang ◽  
Murat O. Arcasoy
Keyword(s):  
Breast Cancer ◽  
Cell Migration ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Fold Increase ◽  
Transfected Cells ◽  
Akt Phosphorylation ◽  
And Migration ◽  
Epor Expression ◽  
Proliferation And Migration

Abstract The ubiquitous expression of the EPO receptor (EpoR) in various non-hematopoietic tissues is associated with broad EPO-mediated tissue-protective effects. The role of EpoR expression in tumor cells and its potential for contribution to tumor biology and progression requires further characterization. We investigated whether EpoR expression levels and activation in tumor cells may modulate EPO sensitivity, proliferation and cell migration. MCF-7 breast cancer cells which express endogenous EpoR were engineered to stably express R129C-EpoR, a constitutively active EpoR that confers cytokine-independent hematopoietic cell growth but does not transform fibroblasts. Empty vector-transfected cells were negative controls. In untransfected cells, phosphotyrosine immunoblots showed EPO-induced tyrosine phosphorylation of several cellular proteins. EPO resulted in dose- and time-dependent phosphorylation of ERK1/2, but not JAK2, STAT5 or AKT. Increased EPO-induced ERK phosphorylation was associated with 2.3±0.3-fold increase in ERK kinase activity (P<0.05, n=3). EPO exhibited either a minor effect or no effect on proliferation of MCF-7 cells whereas cell migration in Transwell chambers was significantly stimulated by EPO (P<0.05, n=9). R129C-EpoR expression resulted in 2-fold increase in cellular proliferation (P<0.01, 2 clones, n=6) and 1.5±0.2-fold increase in cellular migration compared to vector controls (P<0.05, 3 clones, n=12). EPO significantly stimulated the migration of empty vector-transfected cells by 1.9±0.2-fold (P<0.001, n=12). Exogenous EPO did not further enhance the increased proliferation and migration of R129C-EpoR cells. We investigated the mechanisms involved in the increased migration of R129C-EpoR cells. Basal phosphorylation of ERK1/2 (2.6±0.4-fold, 3 clones, P<0.05) and AKT (1.6±0.1-fold, P<0.05) were significantly increased compared to vector controls. No changes in the phosphorylation status of JAK2, STAT5, JAK1 or p38 MAP kinases were observed under basal conditions or in response to EPO. Whereas EPO did not induce AKT phosphorylation in untransfected or vector-transfected cells, in R129C-EpoR cells, there was a significant, dose-dependent increase in AKT phosphorylation in response to EPO (3.29±0.5-fold, n=3 clones, P<0.05). In R129C-EpoR cells, EPO significantly enhanced ERK1/2 phosphorylation 2.7±0.3 fold compared to vector controls (P<0.001). Because c-Jun-NH2-kinase (JNK) is involved in cell migration, we determined the effect of EPO on JNK phosphorylation. EPO markedly increased JNK phosphorylation in R129C-EpoR cells by 5.38±1.6 fold (P<0.001) compared to vector controls in a dose-dependent manner. JNK phosphorylation and increased EPO-induced migration of vector-transfected cells were blocked by treatment with JNK kinase inhibitor SP600125. The increased migration of R129C-EpoR cells in the absence of exogenous EPO was also blocked by SP600126. These data indicate that -EPO promotes the migration of breast cancer cells through a JNK-kinase dependent signaling pathway -Expression of R129C-EpoR promotes the proliferation and migration of breast cancer cells -EPO sensitivity is enhanced by R129C-EpoR expression leading to restoration of EPO-dependent AKT phosphorylation and increased ERK1/2 and JNK kinase phosphorylation -The biologic effects of EPO in breast cancer cells are mediated through JAK2-STAT5 axis-independent signaling pathways -EpoR expression levels in tumor cells may modulate tumor cell proliferation and migration responses.

scholarly journals PTEN and Other PtdIns(3,4,5)P3 Lipid Phosphatases in Breast Cancer

2020 ◽  
Vol 21 (23) ◽  
pp. 9189
Author(s):  
Mariah P. Csolle ◽  
Lisa M. Ooms ◽  
Antonella Papa ◽  
Christina A. Mitchell
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Invasive Disease ◽  
Breast Cancers ◽  
Inositol Polyphosphate ◽  
Akt Phosphorylation ◽  
Lipid Phosphatases ◽  
And Migration ◽  
Phosphoinositide 3 Kinase

The phosphoinositide 3-kinase (PI3K)/AKT signalling pathway is hyperactivated in ~70% of breast cancers. Class I PI3K generates PtdIns(3,4,5)P3 at the plasma membrane in response to growth factor stimulation, leading to AKT activation to drive cell proliferation, survival and migration. PTEN negatively regulates PI3K/AKT signalling by dephosphorylating PtdIns(3,4,5)P3 to form PtdIns(4,5)P2. PtdIns(3,4,5)P3 can also be hydrolysed by the inositol polyphosphate 5-phosphatases (5-phosphatases) to produce PtdIns(3,4)P2. Interestingly, while PTEN is a bona fide tumour suppressor and is frequently mutated/lost in breast cancer, 5-phosphatases such as PIPP, SHIP2 and SYNJ2, have demonstrated more diverse roles in regulating mammary tumourigenesis. Reduced PIPP expression is associated with triple negative breast cancers and reduced relapse-free and overall survival. Although PIPP depletion enhances AKT phosphorylation and supports tumour growth, this also inhibits cell migration and metastasis in vivo, in a breast cancer oncogene-driven murine model. Paradoxically, SHIP2 and SYNJ2 are increased in primary breast tumours, which correlates with invasive disease and reduced survival. SHIP2 or SYNJ2 overexpression promotes breast tumourigenesis via AKT-dependent and independent mechanisms. This review will discuss how PTEN, PIPP, SHIP2 and SYNJ2 distinctly regulate multiple functional targets, and the mechanisms by which dysregulation of these distinct phosphoinositide phosphatases differentially affect breast cancer progression.

scholarly journals MicroRNA-488 inhibits proliferation and motility of tumor cells via downregulating FSCN1, modulated by Notch3 in breast carcinomas

2020 ◽  
Vol 11 (10) ◽  
Author(s):  
Yang Wu ◽  
Ming-Heng Yuan ◽  
Hua-Tao Wu ◽  
Wen-Jia Chen ◽  
Man-Li Zhang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Suppressor ◽  
Malignant Tumors ◽  
Luciferase Assay ◽  
Breast Cancers ◽  
Breast Carcinomas ◽  
Translation Process ◽  
Physiological Processes ◽  
And Migration ◽  
Proliferation And Migration

Abstract As important modulators in multiple physiological processes, microRNAs (miRNAs) have been reported in various malignant tumors, including breast cancer. The current study investigated the function of a new tumor suppressor microRNA, miR-488, and its molecular mechanism of metastasis in breast cancers. CCK8 and transwell assays revealed that the upregulated miR-488 level significantly inhibited the proliferation and migration of breast cancer cells. As a potential downstream gene, the mRNA and protein level of FSCN1 was suppressed by increased miR-488 and vice versa. Luciferase assay showed that miR-488 directly bind to the 3′UTR of FSCN1 and suppressed the translation process of FSCN1. The promoter region of miR-488 was directly bound by Notch3 and promoted the expression of miR-488 transcriptionally. Immunohistochemistry results revealed that in patients with breast cancer, the expression of Notch3 and were negatively correlated with the FSCN1 levels significantly. Therefore, the current finding predicted miR-488 as a tumor suppressor molecule in breast cancer, and demonstrated that Notch3/miR-488/FSCN1 axis is established and involved in regulating the metastasis of breast cancers, providing novel therapeutic targets for patients with breast cancers.

scholarly journals Risk factors for breast cancer development by tumor characteristics among women with benign breast disease

2021 ◽  
Vol 23 (1) ◽  
Author(s):  
Jonine D. Figueroa ◽  
Gretchen L. Gierach ◽  
Máire A. Duggan ◽  
Shaoqi Fan ◽  
Ruth M. Pfeiffer ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Risk ◽  
Fold Increase ◽  
Tumor Grade ◽  
Breast Disease ◽  
Breast Cancers ◽  
Increased Risk ◽  
Er Positive ◽  
Proliferative Bbd

Abstract Background Among women diagnosed with invasive breast cancer, 30% have a prior diagnosis of benign breast disease (BBD). Thus, it is important to identify factors among BBD patients that elevate invasive cancer risk. In the general population, risk factors differ in their associations by clinical pathologic features; however, whether women with BBD show etiologic heterogeneity in the types of breast cancers they develop remains unknown. Methods Using a nested case-control study of BBD and breast cancer risk conducted in a community healthcare plan (Kaiser Permanente Northwest), we assessed relationships of histologic features in BBD biopsies and patient characteristics with subsequent breast cancer risk and tested for heterogeneity of associations by estrogen receptor (ER) status, tumor grade, and size. The study included 514 invasive breast cancer cases (median follow-up of 9 years post-BBD diagnosis) and 514 matched controls, diagnosed with proliferative or non-proliferative BBD between 1971 and 2006, with follow-up through mid-2015. Odds ratios (ORs) and 95% confidence intervals (CIs) were obtained using multivariable polytomous logistic regression models. Results Breast cancers were predominantly ER-positive (86%), well or moderately differentiated (73%), small (74% < 20 mm), and stage I/II (91%). Compared to patients with non-proliferative BBD, proliferative BBD with atypia conferred increased risk for ER-positive cancer (OR = 5.48, 95% CI = 2.14–14.01) with only one ER-negative case, P-heterogeneity = 0.45. The presence of columnar cell lesions (CCLs) at BBD diagnosis was associated with a 1.5-fold increase in the risk of both ER-positive and ER-negative tumors, with a 2-fold increase (95% CI = 1.21–3.58) observed among postmenopausal women (56%), independent of proliferative BBD status with and without atypia. We did not identify statistically significant differences in risk factor associations by tumor grade or size. Conclusion Most tumors that developed after a BBD diagnosis in this cohort were highly treatable low-stage ER-positive tumors. CCL in BBD biopsies may be associated with moderately increased risk, independent of BBD histology, and irrespective of ER status.

scholarly journals The Potential Utility of Curcumin in the Treatment of HER-2-Overexpressed Breast Cancer: AnIn VitroandIn VivoComparison Study with Herceptin

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Hung-Wen Lai ◽  
Su-Yu Chien ◽  
Shou-Jen Kuo ◽  
Ling-Ming Tseng ◽  
Hui-Yi Lin ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Signal Transduction ◽  
Cell Growth ◽  
Xenograft Model ◽  
Breast Cancer Cell Lines ◽  
Breast Cancers ◽  
Her 2 ◽  
Mcf 7

HER-2 is an important oncoprotein overexpressed in about 15–25% of breast cancers. We hypothesized that the ability of curcumin to downregulate HER-2 oncoprotein and inhibit the signal transduction pathway of PI3K/Akt, MAPK, and NF-κB activation may be important in the treatment of HER-2-overexpressed breast cancer. To examine the effect of curcumin on breast cancer cells, MCF-7, MDA-MB-231, MCF-10A, BT-474, and SK-BR-3-hr (a herceptin resistant strain from SK-BR-3) cells were used forin vitroanalysis. Thein vivoeffect of curcumin on HER-2-overexpressed breast cancer was investigated with the HER-2-overexpressed BT-474 xenograft model. Cell growth, cell cycle change, the antimobility effect, signal transduction, and xenograft volume analysis between groups treated with herceptin and/or curcumin were tested. Curcumin decreased the cell growth of various breast cancer cell lines (MCF-7, MDA-MB-231, MCF-10A, BT-474, and SK-BR-3-hr). In Western blot analysis, the phosphorylation of Akt, MAPK, and expression of NF-κB were reduced in BT-474 cells, but not in SK-BR-3-hr cells, after treatment with herceptin. When treated with curcumin, the HER-2 oncoprotein, phosphorylation of Akt, MAPK and expression of NF-κB were decreased in both BT-474 and SK-BR-3-hr cells. In the BT-474 xenograft model, though not as much as herceptin, curcumin did effectively decrease the tumor size. The combination of curcumin with herceptin was not better than herceptin alone; however, the combination of taxol and curcumin had an antitumor effect comparable with taxol and herceptin. The results suggested that curcumin has potential as a treatment for HER-2-overexpressed breast cancer.

scholarly journals Antiproliferative and Antimigration Activities of Fluoro-Neplanocin A via Inhibition of Histone H3 Methylation in Triple-Negative Breast Cancer

Biomolecules ◽  
2020 ◽  
Vol 10 (4) ◽  
pp. 530 ◽  
Author(s):  
Woong Sub Byun ◽  
Won Kyung Kim ◽  
Ji-seong Yoon ◽  
Dnyandev B. Jarhad ◽  
Lak Shin Jeong ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Histone H3 ◽  
Normal Breast ◽  
Migration And Invasion ◽  
Potential Candidate ◽  
Breast Cancers ◽  
Neplanocin A ◽  
Tnbc Cell

Triple-negative breast cancer (TNBC) is among the most aggressive and potentially metastatic malignancies. Most affected patients have poor clinical outcomes due to the lack of specific molecular targets on tumor cells. The upregulated expression of disruptor of telomeric silencing 1-like (DOT1L), a histone methyltransferase specific for the histone H3 lysine 79 residue (H3K79), is strongly correlated with TNBC cell aggressiveness. Therefore, DOT1L is considered a potential molecular target in TNBC. Fluoro-neplanocin A (F-NepA), an inhibitor of S-adenosylhomocysteine hydrolase, exhibited potent antiproliferative activity against various types of cancer cells, including breast cancers. However, the molecular mechanism underlying the anticancer activity of F-NepA in TNBC cells remains to be elucidated. We determined that F-NepA exhibited a higher growth-inhibitory activity against TNBC cells relative to non-TNBC breast cancer and normal breast epithelial cells. Moreover, F-NepA effectively downregulated the level of H3K79me2 in MDA-MB-231 TNBC cells by inhibiting DOT1L activity. F-NepA also significantly inhibited TNBC cell migration and invasion. These activities of F-NepA might be associated with the upregulation of E-cadherin and downregulation of N-cadherin and Vimentin in TNBC cells. Taken together, these data highlight F-NepA as a strong potential candidate for the targeted treatment of high-DOT1L-expressing TNBC.

scholarly journals Metastasis-suppressor NME1 controls the invasive switch of breast cancer by regulating MT1-MMP surface clearance

Oncogene ◽  
2021 ◽  
Author(s):  
Catalina Lodillinsky ◽  
Laetitia Fuhrmann ◽  
Marie Irondelle ◽  
Olena Pylypenko ◽  
Xiao-Yan Li ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Plasma Membrane ◽  
Cancer Progression ◽  
Ductal Carcinoma ◽  
Xenograft Model ◽  
Breast Tumors ◽  
Endocytic Pathway ◽  
Metastasis Suppressor ◽  
Breast Cancers

AbstractMembrane Type 1 Matrix Metalloprotease (MT1-MMP) contributes to the invasive progression of breast cancers by degrading extracellular matrix tissues. Nucleoside diphosphate kinase, NME1/NM23-H1, has been identified as a metastasis suppressor; however, its contribution to local invasion in breast cancer is not known. Here, we report that NME1 is up-regulated in ductal carcinoma in situ (DCIS) as compared to normal breast epithelial tissues. NME1 levels drop in microinvasive and invasive components of breast tumor cells relative to synchronous DCIS foci. We find a strong anti-correlation between NME1 and plasma membrane MT1-MMP levels in the invasive components of breast tumors, particularly in aggressive histological grade III and triple-negative breast cancers. Knockout of NME1 accelerates the invasive transition of breast tumors in the intraductal xenograft model. At the mechanistic level, we find that MT1-MMP, NME1 and dynamin-2, a GTPase known to require GTP production by NME1 for its membrane fission activity in the endocytic pathway, interact in clathrin-coated vesicles at the plasma membrane. Loss of NME1 function increases MT1-MMP surface levels by inhibiting endocytic clearance. As a consequence, the ECM degradation and invasive potentials of breast cancer cells are enhanced. This study identifies the down-modulation of NME1 as a potent driver of the in situ-to invasive transition during breast cancer progression.

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