染色质重塑蛋白MORC2通过调节ALDH1A3表达促进乳腺癌细胞的干性

背景与目的:染色质重塑蛋白MORC家族CW型锌指结构蛋白2(microrchidia family CW-type zinc finger 2,MORC2)在DNA介导的基因转录及DNA损伤修复等基本生物学过程中发挥重要作用,但其对乳腺癌细胞生物学行为的影响目前尚无相关报道.乙醛脱氢酶(aldehyde dehydrogenase,ALDH)家族成员ALDH1A3(alde-hyde dehydrogenase family 1 member A3,ALDH1A3)是一种公认的乳腺癌干细胞的标志物,但其在乳腺癌细胞中的调控机制目前尚不清楚.该研究拟探讨敲低MORC2基因对ALDH1A3表达以及对乳腺癌细胞干性的影响.方法:利用短发夹RNA(short hairpin RNA,shRNA)介导的基因沉默方法构建稳定敲低MORC2基因的乳腺癌细胞系;利用实时荧光定量聚合酶链反应(real-time fluorescent quantitative polymerase chain reaction,RTFQ-PCR)和蛋白[质]印迹法(Western blot)分析敲低MORC2基因对ALDH1A3表达的影响;利用微球体形成实验和流式细胞荧光分选技术(fluorescence activated cell sorting,FACS)分析敲低MORC2对乳腺癌干细胞亚群的影响.结果:Western blot和RTFQ-PCR分析结果显示,敲低MORC2基因显著下调ALDH1A3蛋白及mRNA水平;微球体形成实验显示敲低MORC2基因显著抑制MCF-7细胞的成球能力;FACS分析显示敲低MORC2基因显著下调ALDH1A3阳性乳腺癌干细胞亚群,而对CD44+CD24-乳腺癌干细胞亚群没有明显影响.结论:MORC2通过调节ALDH1A3的表达促进乳腺癌干细胞表型.     

HER-2通过ZEB1促进乳腺癌细胞上皮间质转化

背景与目的：人类表皮生长因子受体2(human epidermal growth factor receptor-2,HER-2)是表皮生长因子受体家族中的一员,它参与细胞多个生物过程,如细胞增殖、侵袭和凋亡等。有研究表明,HER-2与细胞上皮间质转化(epithelial-mesenchymal transition,EMT)过程相关,但具体机制有待进一步探讨,本研究旨在探讨HER-2对EMT的调节机制。方法：用Transwell小室模拟细胞的迁徙侵袭能力;采用实时荧光定量聚合酶链反应(real-time lfuorescent quantitative polymerase chain reaction,RTFQ-PCR)检测目的基因的表达;用活性氧检测试剂盒检测细胞活性氧的水平。结果：Transwell小室模拟实验发现,HER-2过表达能促进乳腺癌细胞的侵袭转移;机制研究表明,HER-2能上调ZEB1,用siRNA降低ZEB1表达使HER-2过表达细胞的侵袭能力受损;此外,HER-2过表达乳腺癌细胞中活性氧水平较低。结论：HER-2可以上调ZEB1的表达而赋予乳腺癌细胞EMT相关特性,ZEB1可作为进一步研究HER-2与EMT调节关系的靶点。     

Leukocyte migration inhibition in relation to nuclear pleomorphism and lymphoid infiltration in breast cancer

Leukocyte migration inhibition (LMI) in patients with breast cancer was examined by using 3 M-KCl tissue extracts of breast tumors. Tumor extracts were obtained from 12 breast carcinomas of various histological types. In 20 of 65 (30.8%) leukocyte preparations from 25 patients with breast cancer migration was inhibited by breast cancer tissue extracts. In 26 leukocyte preparations from eight healthy persons and 22 preparations from eight patients with benign diseases of the breast migration was not inhibited by the breast cancer extracts. In only two of 47 (4.3%) leukocyte preparations from 12 patients with other cancers migration was inhibited by the extracts. The occurrence of LMI was the highest in leukocytes from the patients with breast cancer showing marked nuclear pleomorphism (10/19, 52.6%) or showing marked mononuclear cell infiltration (6/12, 50.0%). These results suggest that 3 M-KCl tissue extracts of breast cancer may contain tumor-associated antigens in solubilized form and that there may be a correlation between LMI and nuclear pleomorphism of cancer cells of the leukocyte donor as well as mononuclear cell infiltration in the tumor of the leukocyte donor.     

NFAT蛋白各亚型在食管鳞癌组织中的表达与临床病理因素间的关系

背景与目的：研究发现,活化T细胞核因子(nuclear factor of activated T cells,NFAT)与多种恶性肿瘤关系密切,食管鳞癌是我国最常见的恶性肿瘤之一。本研究探讨食管鳞癌组织NFAT各亚型的表达及其与食管鳞癌各临床病理因素的关系。方法：采用免疫组化法检测104例食管鳞癌组织和癌旁食管黏膜组织中NFAT各亚型的表达情况。结果：NFAT1～4在食管鳞癌组织中阳性表达率分别为53.8%、10.6%、26.9%和45.2%,与在癌旁食管黏膜组织中的表达差异有统计学意义(P<0.001)。NFAT1的表达与饮酒史(62.3% vs 37.1%,P=0.01)、淋巴结转移(68.4% vs 5.5%,P=0.002)及较晚的分期(58.7% vs 36.2%,P=0.02)密切相关,多因素分析提示NFAT1过表达仅与淋巴结转移相关。淋巴结转移者的NFAT3表达率(39.4%)明显高于无淋巴结转移者(19.7%)。结论：NFAT蛋白在食管鳞癌组织中过表达,NFAT1与NFAT3的表达率与淋巴结转移密切相关,可能在肿瘤的发生、发展中起一定作用。     

Failure of neutrophil chemotactic function in breast cancer patients treated with chemotherapy

Neutrophil migration is a key host event against infection. Chemotherapy may alter neutrophil function and favor increased risk of infection. Herein, we investigated the effect of chemotherapy on the migration capacity of circulating neutrophils obtained from breast cancer patients and mechanisms involved in this event. Breast cancer women (n=23) at disease stage I–III and healthy control women (n=25) were prospectively enrolled. No differences in the in vitro migratory responses towards the chemotactic stimuli N-formyl- L-methionyl- L-leucyl- L-phenylalanine (fMLP), leukotriene B₄ (LTB₄) and interleukin (IL)-8 were observed in purified neutrophils from controls and patients, in a microchemotaxis chamber assay. However, the migration capacity evaluated upon chemotherapy (5-fluoruracil, adriamycin and cyclophosphamide, 21-day intervals between cycles, total leukocyte count ≥2,000/mm³), on the day immediately before the beginning of the sixth cycle, showed that patient neutrophils (n=14) failed to migrate in response to fMLP compared to response observed upon diagnosis. Considering patients (n=8) with documented bacterial infection between cycles, the number of migrated neutrophils (mean±SD) compared to response at diagnosis was markedly reduced upon chemotherapy to either fMLP (30.1±8.26 vs. 2.81±1.28) or LTB₄ (15.72±4.8 vs. 2.8±1.64) stimuli respectively. Treatment of control neutrophils with sera of chemotherapy-treated patients with infective episodes, to test for the presence of circulating immunosuppressive factors, significantly reduced the migratory capacity of healthy neutrophils to fMLP, LTB₄ and IL-8, in a dose-dependent way. But no significant differences were found in the serum levels of nitric oxide (NO) metabolites, tumor necrosis factor (TNF)-α, IL-6, IL-8 and IL-10 collected at the same time as the collection of blood for neutrophil migration experiments. In conclusion, breast cancer patients showed suppressed neutrophil migratory response upon chemotherapy, accompanied by bacterial infection episodes. Circulating factors are involved, at least partially, in the inhibitory mechanism on neutrophil migration.     

Up-regulation of C1GALT1 promotes breast cancer cell growth through MUC1-C signaling pathway

Aberrant glycosylation is frequently observed in cancers. Core 1 β1,3-galactosyltransferase (C1GALT1) is an exclusive enzyme in humans that catalyzes the biosynthesis of core 1 O-glycan structure, Gal-GalNAc-O-Ser/Thr, whose expression is commonly up-regulated during tumorigenesis. Little is known about the function of C1GALT1 in breast cancer. This study aims to determine the correlation between C1GALT1 expression and breast cancer clinicopathological features and roles of C1GALT1 in breast cancer malignant phenotypes. Public databases and our data showed that C1GALT1 mRNA and C1GALT1 protein are frequently up-regulated in breast cancer; and increased C1GALT1 expression correlates with higher histological grade and advanced tumor stage. Overexpression of C1GALT1 enhanced breast cancer cell growth, migration, and invasion in vitro as well as tumor growth in vivo. Conversely, C1GALT1 knockdown suppressed these malignant phenotypes. Furthermore, C1GALT1 modulates O-glycan structures on Mucin (MUC) 1 and promotes MUC1-C/β-catenin signaling in breast cancer cells. These findings suggest that C1GALT1 enhances breast cancer malignant progression through promoting MUC1-C/β-catenin signaling pathway. Unveiling the function of C1GALT1 in breast cancer opens new insights to the roles of C1GALT1 and O-glycosylation in tumorigenesis and renders the potential of C1GALT1 as a target of novel therapeutic agent development.     

AEG-1基因促进乳腺癌细胞株MCF-7转移

目的 观察AEG-1基因在细胞水平对乳腺癌细胞MCF-7转移的影响。方法 通过将siRNA转染进MCF-7细胞,沉默细胞中AEG-1表达量,以转染阴性siRNA作为对照组。分别采用Transwell小室检测细胞迁移侵袭能力、CCK8实验检测细胞增殖能力。同时通过检测细胞中VEGF的变化及HUVEC细胞体外管腔形成实验考察AEG-1对于血管新生的影响。结果 沉默AEG-1,MCF-7细胞的迁移能力、侵袭能力和增殖能力明显受到抑制。沉默AEG-1,MCF-7细胞的VEGF表达明显降低。上清处理HUVEC细胞,沉默AEG-1组的血管新生能力明显受到抑制。结论 沉默AEG-1基因能显著抑制MCF-7细胞转移的多个层面,包括细胞迁移、侵袭、增殖以及血管新生。表明AEG-1基因在乳腺癌转移过程中起着重要作用,也为将来乳腺癌治疗开拓了新思路。     

Cathepsin C promotes breast cancer lung metastasis by modulating neutrophil infiltration and neutrophil extracellular trap formation

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Deficiency in surface expression of E-selectin ligand promotes lung colonization in a mouse model of breast cancer

Expression of sialyl Lewis(x) (sLe(x)) and sLe(a) on tumor cells is thought to facilitate metastasis by promoting cell adhesion to selectins on vascular endothelial cells. Experiments supporting this concept usually bypass the early steps of the metastatic process by employing tumor cells that are injected directly into the blood. We investigated the relative role of sLe(x) oligosaccharide in the dissemination of breast carcinoma, employing a spontaneous murine metastasis model. An sLe(x) deficient subpopulation of the 4T1 mammary carcinoma cell line was produced by negative selection using the sLe(x)-reactive KM93 MAb. This subpopulation was negative for E-selectin binding but retained P-selectin binding. Both sLe(x)-negative and -positive cells grew at the same rate; however, sLe(x)-negative cells spread more efficiently on plates and had greater motility in wound-scratch assays. Mice inoculated in the mammary fat pad with sLe(x)-negative and -positive variants produced lung metastases. However, the number of lung metastases was significantly increased in the group inoculated with the sLe(x)-negative variant (p = 0.0031), indicating that negative selection for the sLe(x) epitope resulted in enrichment for a subpopulation of cells with a high metastatic phenotype. Cell variants demonstrated significant differences in cellular morphology and pattern of tumor growth in primary and secondary tumor sites. These results strongly suggest that loss of sLe(x) may facilitate the metastatic process by contributing to escape from the primary tumor mass.     

Prognostic implication of p53 protein expression in relation to nuclear pleomorphism and the MIB-1 counts in breast cancer

BACKGROUND: A close correlation of the p53 protein expression to nuclear pleomorphism and proliferative activity in breast cancer has been reported. The prognostic implications of p53 protein expression, however, in relation to nuclear pleomorphism and proliferative activity in breast cancer remain controversial. PATIENTS AND METHODS: Nuclear pleomorphism and immunohistochemical reactivity for p53 protein and MIB-1 were evaluated on formalin-fixed paraffin-stored sections from 250 patients with breast cancer for whom the median follow-up duration was 6.4 years. RESULTS: p53 protein expression was positive in 66 (26.4%) of 250 cases. Nuclear pleomorphism was grade I or II in 169 (67.6%) cases and grade III in 81(32.4%)cases. The MIB-1 counts were more than 10% in 102 (40.8%) cases and less than 10% in 148 (59.2%) cases. There was a close correlation between p53 protein expression and nuclear pleomorphism (p<0.0001) and between p53 protein expression and MIB-1 counts (p<0.0001). Univariate analyses showed the 66 cases with positive p53 protein expression to have a significantly (p=0.0284) worse disease free survival (DFS) than the 184 cases with negative p53 protein expression. A multivariate analysis, however, on the variables including all of p53 protein expression, nuclear pleomorphism and MIB-1 counts indicated the MIB-1 counts (p=0.0041) as well as the lymph node status to be independently significant factors for DFS, while neither p53 protein expression nor nuclear pleomorphism were independently significant factors for DFS. CONCLUSION: The present study demonstrated that the p53 protein expression, nuclear pleomorphism and MIB-1 counts all demonstrated prognostic significance for breast cancer, while the most significant prognostic indicator among these three biological parameters was the MIB-1 counts.     

PARP1通过调节RNF144A抑制乳腺癌细胞凋亡

背景与目的：乳腺癌是全球女性最常见的恶性肿瘤，但其发病机制尚不清楚。我们前期研究发现环指蛋白144A（ring finger protein 144A，RNF144A）调节多聚ADP核糖聚合酶1［poly（ADP ribose）polymerase 1，PARP1］的稳定性，进而影响乳腺癌细胞对PARP抑制剂olaparib的敏感性。该研究旨在探讨PARP1是否对RNF144A具有调节作用及其对乳腺癌细胞凋亡的影响。方法：利用免疫组织化学方法检测乳腺癌组织中PARP1的表达水平，并分析PARP1表达水平与乳腺癌患者预后的关系。采用蛋白质印迹法（Western blot）检测过表达或者敲低PARP1对RNF144A蛋白水平的影响。采用实时荧光定量聚合酶链反应（real-time fluorescent quantitative polymerase chain reaction，RTFQ-PCR）检测敲低PARP1对RNF144A转录水平的影响。利用AnnexinⅤ-PE/7-AAD双染法流式细胞术检测细胞凋亡。结果：在乳腺癌组织中PARP1表达阳性率为68%，且高表达PARP1的患者预后较差。在敲低或过表达PARP1的HEK-293T和乳腺癌细胞中，RNF144A在mRNA水平无明显变化，但其蛋白水平与PARP1表达呈负相关。Olaparib诱导细胞凋亡时，过表达PARP1细胞凋亡率较低，在过表达PARP1的细胞中重新过表达RNF144A后凋亡率有一定程度的恢复。结论：PARP1在乳腺癌细胞的表达水平与乳腺癌患者的预后相关，可能在乳腺癌的发生、发展中扮演着癌基因的角色。PARP1调节RNF144A的蛋白水平但不影响其mRNA水平。PARP1可能通过负向调节RNF144A抑制乳腺癌细胞凋亡。     

FOXA1 expression affects the proliferation activity of luminal breast cancer stem cell populations

The expression of estrogen receptor is the key in most breast cancers (BC) and binding of estrogen receptor to the genome correlates to Forkhead protein (FOXA1) expression. We herein assessed the correlation between the cancer stem cell (CSC) population and FOXA1 expression in luminal BC. We established luminal BC cells derived from metastatic pleural effusion and analyzed the potency of CSC and related factors with established luminal BC cell lines. We also confirmed that mammosphere cultures have an increased aldehyde dehydrogenase‐positive population, which is one of the CSC markers, compared with adherent culture cells. Using a quantitative PCR analysis, we found that mammosphere forming cells showed a higher expression of FOXA1 and stemness‐related genes compared with adherent culture cells. Furthermore, the growth activity and colony‐forming activity of 4‐hydroxytamoxifen‐treated BC cells were inhibited in a mammosphere assay. Interestingly, 4‐hydroxytamoxifen‐resistant cells had significantly increased FOXA1 gene expression levels. Finally, we established short hairpin RNA of FOXA1 (shFOXA1) MCF‐7 cells and investigated the relationship between self‐renewal potential and FOXA1 expression. As a result, we found no significant difference in the number of mammospheres but decreased colony formation in shFOXA1 MCF‐7 cells compared with control. These results suggest that the expression of FOXA1 appears to be involved in the proliferation of immature BC cells rather than the induction of stemness‐related genes and self‐renewal potency of CSCs.     

PD-L1+ dendritic cells in the tumor microenvironment correlate with good prognosis and CD8+ T cell infiltration in colon cancer

BackgroundThe prognostic value of tumor‐associated dendritic cells (DC) in colon cancer remains poorly understood. This may be in part due to the interchangeable expression of immunostimulatory and immunoinhibitory molecules on DC. Here we investigated the prognostic impact of CD11c⁺ DC co–expressing the immunoinhibitory molecule PD‐L1 and their spatial relationship with CD8⁺ T‐cells in patients treated for stage III colon cancer.MethodsTissue microarrays containing representative cores of central tumor, leading edge, and adjacent normal tissue from 221 patients with stage III colon cancer were immunostained for CD8, CD11c, PD‐L1, and cytokeratin using immunofluorescent probes. Cells were quantified using StrataQuest digital image analysis software, with intratumoral and stromal regions analyzed separately. Kaplan‐Meier estimates and Cox regression were used to assess survival.ResultsIntratumoral CD8⁺ cell density (HR = .52, 95% confidence interval [CI] .33‐.83, P = .007), stromal CD11c⁺ cell density (HR = .52, 95% CI .33‐.83, P = .006), intratumoral CD11c⁺PD‐L1⁺ cell density (HR = .57, 95% CI .35‐.92, P = .021), and stromal CD11c⁺PD‐L1⁺ cell density (HR = .48, 95% CI .30‐.77, P = .003) on leading‐edge cores were all significantly associated with good survival. CD8⁺ cell density was positively correlated with both CD11c⁺ cell density and CD11c⁺PD‐L1⁺ cell density in tumor epithelium and stromal compartments.ConclusionHere we showed that PD‐L1‐expressing DC in the tumor microenvironment are associated with improved survival in stage III colon cancer and likely reflect an immunologically “hot” tumor microenvironment. Further investigation into the expression of immunomodulatory molecules by tumor‐associated DC may help to further elucidate their prognostic value.     

Interleukin‐33/ST2 axis promotes breast cancer growth and metastases by facilitating intratumoral accumulation of immunosuppressive and innate lymphoid cells

The role of IL‐33/ST2 pathway in antitumor immunity is unclear. Using 4T1 breast cancer model we demonstrate time‐dependent increase of endogenous IL‐33 at both the mRNA and protein levels in primary tumors and metastatic lungs during cancer progression. Administration of IL‐33 accelerated tumor growth and development of lung and liver metastases, which was associated with increased intratumoral accumulation of CD11b⁺Gr‐1⁺ TGF‐β1⁺ myeloid‐derived suppressor cells (MDSCs) that expressed IL‐13α1R, IL‐13‐producing Lin^?Sca‐1⁺ST2⁺ innate lymphoid cells (ILCs) and CD4⁺Foxp3⁺ST2⁺IL‐10⁺ Tregs compared to untreated mice. Higher incidence of monocytic vs. granulocytic MDSCs and plasmocytoid vs. conventional dendritic cells (DCs) was present in mammary tumors of IL‐33‐treated mice. Intratumoral NKp46⁺NKG2D⁺ and NKp46⁺FasL⁺ cells were markedly reduced after IL‐33 treatment, while phosphate‐buffered saline‐treated ST2‐deficient mice had increased frequencies of these tumoricidal natural killer (NK) cells compared to untreated wild‐type mice. IL‐33 promoted intratumoral cell proliferation and neovascularization, which was attenuated in the absence of ST2. Tumor‐bearing mice given IL‐33 had increased percentages of splenic MDSCs, Lin^?Sca‐1⁺ ILCs, IL‐10‐expressing CD11c⁺ DCs and alternatively activated M2 macrophages and higher circulating levels of IL‐10 and IL‐13. A significantly reduced NK cell, but not CD8⁺ T‐cell cytotoxicity in IL‐33‐treated mice was observed and the mammary tumor progression was not affected when CD8⁺ T cells were in vivo depleted. We show a previously unrecognized role for IL‐33 in promoting breast cancer progression through increased intratumoral accumulation of immunosuppressive cells and by diminishing innate antitumor immunity. Therefore, IL‐33 may be considered as an important mediator in the regulation of breast cancer progression.     

Alcohol promotes breast cancer cell invasion by regulating the Nm23-ITGA5 pathway

Background

Alcohol consumption is an established risk factor for breast cancer metastasis. Yet, the mechanism by which alcohol promotes breast cancer metastases is unknown. The ability of cancer cells to invade through tissue barriers (such as basement membrane and interstitial stroma) is an essential step towards establishing cancer metastasis. In the present study, we identify and examine the roles of two genes, Nm23 and ITGA5, in alcohol-induced breast cancer cell invasion.

Methods

Human breast cancer T47D cells were treated with ethanol at various concentrations. Boyden chamber invasion assays were used to measure cellular invasive ability. The mRNA expression level of metastasis suppressor genes including Nm23 was determined by qRT-PCR. ITGA5 was identified using a qRT-PCR array of 84 genes important for cell-cell and cell-extracellular matrix interactions. Nm23 overexpression in addition to Nm23- and ITGA5 knock-down were used to determine the role of the Nm23-ITGA5 pathway on cellular invasive ability of T47D cells. Protein expression levels were verified by Western blot.

Results

Alcohol increased the invasive ability of human breast cancer T47D cells in a dose-dependent manner through the suppression of the Nm23 metastatic suppressor gene. In turn, Nm23 down-regulation increased expression of fibronectin receptor subunit ITGA5, which subsequently led to increased cellular invasion. Moreover, Nm23 overexpression was effective in suppressing the effects of alcohol on cell invasion. In addition, we show that the effects of alcohol on invasion were also inhibited by knock-down of ITGA5.

Conclusions

Our results suggest that the Nm23-ITGA5 pathway plays a critical role in alcohol-induced breast cancer cell invasion. Thus, regulation of this pathway may potentially be used to prevent the establishment of alcohol-promoted metastases in human breast cancers.     

类泛素化neddylation修饰调控乳腺癌中核纤层蛋白lamin B1的表达

背景与目的:类泛素化neddylation修饰在乳腺癌中的作用鲜有报道。该研究的前期研究发现,抑制neddylation修饰可诱导乳腺癌细胞发生衰老,但具体机制尚未完全阐明。研究报道核纤层蛋白lamin B1缺失可导致细胞衰老。本研究旨在探讨在乳腺癌中,neddylation修饰与lamin B1是否存在相关性及其可能的机制。方法:利用113例乳腺癌患者肿瘤组织制成的组织芯片对neddylation修饰过程中关键蛋白神经前体细胞表达发育下调蛋白8(neural precursor cell expressed developmentally downregulated protein 8,NEDD8)、NEDD8活化酶E1(NEDD8-activating enzyme 1,NAE1)及核纤层蛋白lamin B1进行免疫组织化学染色。采用Spearman rank分析NEDD8和NAE1与lamin B1表达的相关性。采用CRISPR/Cas9技术敲低NEDD8的表达以阻断neddylation修饰,采用蛋白质印迹法(Western blot)检测neddylation修饰对Lamin...     

Analysis of Cdc2 and Cyclin D1 expression in breast cancer by immunoblotting

Cyclins and cyclin-dependent kinases may reflect the status of cell proliferation in cancer tissues. The authors sought to determine whether cdc2 and cyclin D1 are expressed in breast cancer and are useful as prognostic factors. Accumulation of cdc2 and cyclin D1 proteins was examined in 88 cases of breast cancer using immunoblotting techniques and correlations with clinicopathological factors and prognoses were investigated. Cdc2 and cyclin D1 proteins were observed in 27.3% and 75.0% of breast cancers studied, respectively. The incidence of lymph node metastasis was significantly high in cdc2/cyclin D1-double positive group and low in double negative group. On the other hand, the incidence of estrogen receptor (ER) negative cases was significantly higher in the cdc2-positive/cyclin D1-negative group. Relapse-free survival times of cdc2-positive cases were significantly shorter than those of cdc2-negative cases. The relapse-free survival times of cyclin D1-positive cases also tended to be poorer than those of cyclin D1-negative cases. Multivariate analyses revealed cdc2 as the second most significant of the prognostic variables, following lymph node status. The three-year relapse-free survival rate of cdc2/cyclin D1-double positive cases was 58.9%, whereas that of cdc2/cyclin D1-double negative cases was 100%. Cdc2 and cyclin D1 represent the status of cell proliferation in breast cancer, and may be useful in breast cancer assessment.     

HMGA1 promotes metastatic processes in basal-like breast cancer regulating EMT and stemness

Breast cancer is a heterogeneous disease that progresses to the critical hallmark of metastasis. In the present study, we show that the High Mobility Group A1 (HMGA1) protein plays a fundamental role in this process in basal-like breast cancer subtype. HMGA1 knockdown induces the mesenchymal to epithelial transition and dramatically decreases stemness and self-renewal. Notably, HMGA1 depletion in basal-like breast cancer cell lines reduced migration and invasion in vitro and the formation of metastases in vivo. Mechanistically, HMGA1 activated stemness and key migration-associated genes which were linked to the Wnt/beta-catenin, Notch and Pin1/mutant p53 signalling pathways. Moreover, we identified a specific HMGA1 gene expression signature that was activated in a large subset of human primary breast tumours and was associated with poor prognosis. Taken together, these data provide new insights into the role of HMGA1 in the acquisition of aggressive features in breast cancer.