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1.
Br J Cancer ; 131(1): 171-183, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38760444

ABSTRACT

BACKGROUND: Risk of recurrence and progression of ductal carcinoma in situ (DCIS) to invasive cancer remains uncertain, emphasizing the need for developing predictive biomarkers of aggressive DCIS. METHODS: Human cell lines and mouse models of disease progression were analyzed for candidate risk predictive biomarkers identified and validated in two independent DCIS cohorts. RESULTS: RNA profiling of normal mammary and DCIS tissues (n = 48) revealed that elevated SOX11 expression correlates with MKI67, EZH2, and DCIS recurrence score. The 21T human cell line model of DCIS progression to invasive cancer and two mouse models developing mammary intraepithelial neoplasia confirmed the findings. AKT activation correlated with chromatin accessibility and EZH2 enrichment upregulating SOX11 expression. AKT and HER2 inhibitors decreased SOX11 expression along with diminished mammosphere formation. SOX11 was upregulated in HER2+ and basal-like subtypes (P < 0.001). Longitudinal DCIS cohort (n = 194) revealed shorter recurrence-free survival in SOX11+ than SOX11- patients (P = 0.0056 in all DCIS; P < 0.0001 in HER2+ subtype) associated with increased risk of ipsilateral breast event/IBE (HR = 1.9, 95%CI = 1.2-2.9; P = 0.003). DISCUSSION: Epigenetic activation of SOX11 drives recurrence of DCIS and progression to invasive cancer, suggesting SOX11 as a predictive biomarker of IBE.


Subject(s)
Breast Neoplasms , Carcinoma, Intraductal, Noninfiltrating , Disease Progression , Epigenesis, Genetic , Neoplasm Recurrence, Local , SOXC Transcription Factors , Humans , Female , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Breast Neoplasms/metabolism , Animals , Carcinoma, Intraductal, Noninfiltrating/genetics , Carcinoma, Intraductal, Noninfiltrating/pathology , Carcinoma, Intraductal, Noninfiltrating/metabolism , SOXC Transcription Factors/genetics , SOXC Transcription Factors/metabolism , Mice , Neoplasm Recurrence, Local/genetics , Neoplasm Recurrence, Local/pathology , Cell Line, Tumor , Neoplasm Invasiveness , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Gene Expression Regulation, Neoplastic , Receptor, ErbB-2/genetics , Receptor, ErbB-2/metabolism , Enhancer of Zeste Homolog 2 Protein/genetics , Enhancer of Zeste Homolog 2 Protein/metabolism
2.
Sci Signal ; 17(826): eadh4475, 2024 Mar 05.
Article in English | MEDLINE | ID: mdl-38442201

ABSTRACT

The translation elongation factor eEF1A promotes protein synthesis. Its methylation by METTL13 increases its activity, supporting tumor growth. However, in some cancers, a high abundance of eEF1A isoforms is associated with a good prognosis. Here, we found that eEF1A2 exhibited oncogenic or tumor-suppressor functions depending on its interaction with METTL13 or the phosphatase PTEN, respectively. METTL13 and PTEN competed for interaction with eEF1A2 in the same structural domain. PTEN-bound eEF1A2 promoted the ubiquitination and degradation of the mitosis-promoting Aurora kinase A in the S and G2 phases of the cell cycle. eEF1A2 bridged the interactions between the SKP1-CUL1-FBXW7 (SCF) ubiquitin ligase complex, the kinase GSK3ß, and Aurora-A, thereby facilitating the phosphorylation of Aurora-A in a degron site that was recognized by FBXW7. Genetic ablation of Eef1a2 or Pten in mice resulted in a greater abundance of Aurora-A and increased cell cycling in mammary tumors, which was corroborated in breast cancer tissues from patients. Reactivating this pathway using fimepinostat, which relieves inhibitory signaling directed at PTEN and increases FBXW7 expression, combined with inhibiting Aurora-A with alisertib, suppressed breast cancer cell proliferation in culture and tumor growth in vivo. The findings demonstrate a therapeutically exploitable, tumor-suppressive role for eEF1A2 in breast cancer.


Subject(s)
Aurora Kinase A , Breast Neoplasms , Mammary Neoplasms, Animal , PTEN Phosphohydrolase , Peptide Elongation Factor 1 , Animals , Female , Humans , Mice , Aurora Kinase A/genetics , Aurora Kinase A/metabolism , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , F-Box-WD Repeat-Containing Protein 7/genetics , Glycogen Synthase Kinase 3 beta , Mammary Neoplasms, Animal/genetics , Mammary Neoplasms, Animal/metabolism , Mammary Neoplasms, Animal/pathology , PTEN Phosphohydrolase/genetics , PTEN Phosphohydrolase/metabolism , Peptide Elongation Factor 1/genetics , Peptide Elongation Factor 1/metabolism
3.
Future Oncol ; 17(27): 3549-3560, 2021 Sep.
Article in English | MEDLINE | ID: mdl-34154392

ABSTRACT

NKTR-255 is an investigational polyethylene glycol-modified recombinant human IL-15 (rhIL-15) receptor agonist, designed to improve the immunotherapeutic and anti-cancer benefit observed with rhIL-15 while circumventing the toxicities associated with this therapy. In preclinical studies, NKTR-255 has demonstrated enhanced proliferation and function of CD8+ T cells and natural killer cells, as well as enhanced anti-tumor activity and survival both as monotherapy and in combination with monoclonal antibodies in multiple cancer models. Here, we describe the rationale and design of the first-in-human Phase I, dose-escalation and dose-expansion study of NKTR-255 alone and in combination with daratumumab or rituximab in adults with relapsed/refractory multiple myeloma or non-Hodgkin's lymphoma that will determine the maximum tolerated dose and recommended Phase II dose for NKTR-255.


Lay abstract Interleukin-15 (IL-15) is a protein that helps the body's natural immune system to defend itself against infections and diseases like cancer. This article discusses a clinical trial in patients with multiple myeloma or non-Hodgkin's lymphoma that evaluates a new investigational medicine, NKTR-255, a polymer-modified form of IL-15 that has been engineered to improve its ability to provide a sustained anti-tumor immune response. The trial will explore different doses of NKTR-255 to determine patient side effects and to find the highest acceptable dose that patients can tolerate. Based on this, a dose will be chosen that offers an optimal balance between having a positive anti-cancer effect and minimizing side effects. This dose will be tested further in patients who have had different treatments in the past. If the side effects are acceptable, this dose will be tested in a new trial in a large number of patients. Clinical Trial Registration: NCT04136756 (ClinicalTrials.gov).


Subject(s)
Antibodies, Monoclonal/therapeutic use , Antineoplastic Agents/therapeutic use , Hematologic Neoplasms/drug therapy , Interleukin-15/therapeutic use , Rituximab/therapeutic use , Drug Therapy, Combination , Humans , Interleukin-15/chemistry , Polyethylene Glycols/chemistry
4.
EJHaem ; 2(1): 56-65, 2021 Feb.
Article in English | MEDLINE | ID: mdl-35846104

ABSTRACT

We assessed the safety, efficacy, maximum tolerated dose (MTD), and the recommended phase 2 dose (RP2D) of selinexor, a first in class oral selective inhibitor of nuclear export (100 mg once weekly [QW] or 60 mg twice weekly), in combination with daratumumab (16 mg/kg per label) and dexamethasone (40 mg QW) (SDd) in patients with relapsed refractory multiple myeloma (RRMM). Thirty-four patients (median prior therapies, 3 [range, 2-10]) were enrolled; MM was refractory to proteasome inhibitor (PI) in 85%, immunomodulatory agent (IMiD) in 76%, both in 74%, and daratumumab in 6% of patients. Two dose-limiting toxicities (DLTs) were reported in the selinexor 60 mg twice-weekly cohort with no DLTs in the 100 mg QW cohort, making 100 mg QW the MTD and RP2D. Common treatment-related adverse events included thrombocytopenia (70.6%), nausea (70.6%), fatigue (61.8%), anemia (61.8%), and neutropenia (50.0%). Overall response rate was 73% and median progression-free survival 12.5 months in daratumumab-naïve patients. SDd was well tolerated and its promising efficacy suggests that further study of this PI- and IMiD-free regimen in RRMM patients who had at least one prior line of therapy including a PI and an IMiD but whose disease is naïve to daratumumab is warranted.

5.
Sci Rep ; 8(1): 9427, 2018 06 21.
Article in English | MEDLINE | ID: mdl-29930294

ABSTRACT

Inflammatory breast cancer (IBC) is a rare subtype of breast cancer, accounting for 8-10% of breast cancer-associated deaths in the US. Clinical hallmarks of IBC include tumor emboli in lymphatic vessels and E-cadherin overexpression, which supports a type of metastasis referred to as cell cluster-based metastasis, prevalent in IBC. In contrast, we previously reported epithelial-to-mesenchymal transition (EMT)-based progression of IBC, utilizing in vivo xenografts and in vitro Matrigel culture models. To address these two contradictory concepts of IBC metastasis, we used Matrigel culture to induce EMT in a panel of IBC cells. Results revealed Matrigel culture induced vimentin expression in SUM149 and SUM190 IBC cells at the transcriptional and protein levels while maintaining the expression of E-cadherin, a phenomenon referred to as partial EMT. Transcriptional profiling revealed that expression of colony-stimulating factor 1 (CSF-1) was induced in Matrigel culture. When the receptor tyrosine kinase of CSF-1 (CSF-1R) was inhibited by CSF-1R inhibitor BLZ945, the partial EMT was reversed in a dose-dependent manner, indicating that the CSF-1/CSF-1R axis plays a key role in controlling partial EMT. This observation may help reconcile the two contradictory theories of IBC metastasis, EMT vs cell cluster-based metastasis.


Subject(s)
Breast Neoplasms/metabolism , Epithelial-Mesenchymal Transition , Macrophage Colony-Stimulating Factor/metabolism , Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/metabolism , Benzothiazoles/pharmacology , Breast Neoplasms/pathology , Cadherins/genetics , Cadherins/metabolism , Cell Line , Female , Humans , MCF-7 Cells , Picolinic Acids/pharmacology , Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/antagonists & inhibitors , Vimentin/genetics , Vimentin/metabolism
6.
Semin Cell Dev Biol ; 78: 22-36, 2018 06.
Article in English | MEDLINE | ID: mdl-29258963

ABSTRACT

MicroRNAs (miRNAs) are small, non-coding RNAs that regulate gene expression predominantly by inhibiting transcription and/or promoting degradation of target mRNAs also in addition to being involved in non-canonical mechanisms regulating transcription, translation and cell signaling processes. Extracellular secretory miRNAs, either in complex with specific proteins or encapsulated in microvesicles called exosomes, are transported between cells as means of intercellular communication. Secretory miRNAs in circulation remain functional after delivery to recipient cells, regulating target genes and their corresponding signaling pathways. Cancer cell secreted miRNA-mediated intercellular communication affects physiological processes associated with the disease, such as, angiogenesis, metabolic reprogramming, immune modulation, metastasis, and chemo-resistance. Given the stability of miRNAs in body fluids and their well-documented roles in deregulating cancer-relevant genetic pathways, there is considerable interest in developing secretory miRNAs as liquid biopsy biomarkers for detection, diagnosis and prognostication of cancer. In this review, we discuss salient features of miRNA biogenesis, secretion and function in cancer as well as the current state of secretory miRNA isolation and profiling methods. Furthermore, we discuss the challenges and opportunities of secretory miRNA biomarker assay development, which need to be addressed for clinical applications.


Subject(s)
Cell Communication/genetics , Drug Resistance, Neoplasm/genetics , MicroRNAs/genetics , Neoplasm Metastasis/genetics , Neoplasms/genetics , Neovascularization, Pathologic/genetics , Biomarkers, Tumor/genetics , Cell Communication/physiology , Exosomes/metabolism , Humans , Neoplasm Metastasis/pathology , Neoplasms/pathology , Neovascularization, Pathologic/pathology
7.
Front Oncol ; 6: 247, 2016.
Article in English | MEDLINE | ID: mdl-27933271

ABSTRACT

Aurora kinases play critical roles in regulating spindle assembly, chromosome segregation, and cytokinesis to ensure faithful segregation of chromosomes during mitotic cell division cycle. Molecular and cell biological studies have revealed that Aurora kinases, at physiological levels, orchestrate complex sequential cellular processes at distinct subcellular locations through functional interactions with its various substrates. Aberrant expression of Aurora kinases, on the other hand, cause defects in mitotic spindle assembly, checkpoint response activation, and chromosome segregation leading to chromosomal instability. Elevated expression of Aurora kinases correlating with chromosomal instability is frequently detected in human cancers. Recent genomic profiling of about 3000 human cancer tissue specimens to identify various oncogenic signatures in The Cancer Genome Atlas project has reported that recurrent amplification and overexpression of Aurora kinase-A characterize distinct subsets of human tumors across multiple cancer types. Besides the well-characterized canonical pathway interactions of Aurora kinases in regulating assembly of the mitotic apparatus and chromosome segregation, growing evidence also supports the notion that deregulated expression of Aurora kinases in non-canonical pathways drive transformation and genomic instability by antagonizing tumor suppressor and exacerbating oncogenic signaling through direct interactions with critical proteins. Aberrant expression of the Aurora kinases-p53 protein family signaling axes appears to be critical in the abrogation of p53 protein family mediated tumor suppressor pathways frequently deregulated during oncogenic transformation process. Recent findings reveal the existence of feedback regulatory loops in mRNA expression and protein stability of these protein families and their consequences on downstream effectors involved in diverse physiological functions, such as mitotic progression, checkpoint response pathways, as well as self-renewal and pluripotency in embryonic stem cells. While these investigations have focused on the functional consequences of Aurora kinase protein family interactions with wild-type p53 family proteins, those involving Aurora kinases and mutant p53 remain to be elucidated. This article presents a comprehensive review of studies on Aurora kinases-p53 protein family interactions along with a prospective view on the possible functional consequences of Aurora kinase-mutant p53 signaling pathways in tumor cells. Additionally, we also discuss therapeutic implications of these findings in Aurora kinases overexpressing subsets of human tumors.

8.
Carcinogenesis ; 37(12): 1180-1189, 2016 Dec.
Article in English | MEDLINE | ID: mdl-27624071

ABSTRACT

Recent data from The Cancer Genome Atlas analysis have revealed that Aurora kinase A (AURKA) amplification and overexpression characterize a distinct subset of human tumors across multiple cancer types. Although elevated expression of AURKA has been shown to induce oncogenic phenotypes in cells in vitro, findings from transgenic mouse models of Aurora-A overexpression in mammary glands have been distinct depending on the models generated. In the present study, we report that prolonged overexpression of AURKA transgene in mammary epithelium driven by ovine ß-lactoglobulin promoter, activated through multiple pregnancy and lactation cycles, results in the development of mammary adenocarcinomas with alterations in cancer-relevant genes and epithelial-to-mesenchymal transition. The tumor incidence was 38.9% (7/18) in Aurora-A transgenic mice at 16 months of age following 4-5 pregnancy cycles. Aurora-A overexpression in the tumor tissues accompanied activation of Akt, elevation of Cyclin D1, Tpx2 and Plk1 along with downregulation of ERα and p53 proteins, albeit at varying levels. Microarray comparative genomic hybridization (CGH) analyses of transgenic mouse mammary adenocarcinomas revealed copy gain of Glp1r and losses of Ercc5, Pten and Tcf7l2 loci. Review of human breast tumor transcriptomic data sets showed association of these genes at varying levels with Aurora-A gain of function alterations. Whole exome sequencing of the mouse tumors also identified gene mutations detected in Aurora-A overexpressing human breast cancers. Our findings demonstrate that prolonged overexpression of Aurora-A can be a driver somatic genetic event in mammary adenocarcinomas associated with deregulated tumor-relevant pathways in the Aurora-A subset of human breast cancer.


Subject(s)
Adenocarcinoma/genetics , Aurora Kinase A/biosynthesis , Biomarkers, Tumor/biosynthesis , Breast Neoplasms/genetics , Mammary Neoplasms, Animal/genetics , Adenocarcinoma/pathology , Animals , Aurora Kinase A/genetics , Biomarkers, Tumor/genetics , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Epithelium/metabolism , Epithelium/pathology , Female , Gene Expression Regulation, Neoplastic , Humans , Mammary Glands, Animal/metabolism , Mammary Glands, Animal/pathology , Mammary Neoplasms, Animal/pathology , Mice , Neoplasm Proteins/biosynthesis , Pregnancy
9.
Mol Cancer Ther ; 14(12): 2687-99, 2015 Dec.
Article in English | MEDLINE | ID: mdl-26443806

ABSTRACT

Currently, no targeted drug is available for triple-negative breast cancer (TNBC), an aggressive breast cancer that does not express estrogen receptor, progesterone receptor, or HER2. TNBC has high mitotic activity, and, because Aurora A and B mitotic kinases drive cell division and are overexpressed in tumors with a high mitotic index, we hypothesized that inhibiting Aurora A and B produces a significant antitumor effect in TNBC. We tested this hypothesis by determining the antitumor effects of KW-2450, a multikinase inhibitor of both Aurora A and B kinases. We observed significant inhibitory activities of KW-2450 on cell viability, apoptosis, colony formation in agar, and mammosphere formation in TNBC cells. The growth of TNBC xenografts was significantly inhibited with KW-2450. In cell-cycle analysis, KW-2450 induced tetraploid accumulation followed by apoptosis or surviving octaploid (8N) cells, depending on dose. These phenotypes resembled those of Aurora B knockdown and complete pharmaceutical inhibition of Aurora A. We demonstrated that 8N cells resulting from KW-2450 treatment depended on the activation of mitogen-activated protein kinase kinase (MEK) for their survival. When treated with the MEK inhibitor selumetinib combined with KW-2450, compared with KW-2450 alone, the 8N cell population was significantly reduced and apoptosis was increased. Indeed, this combination showed synergistic antitumor effect in SUM149 TNBC xenografts. Collectively, Aurora A and B inhibition had a significant antitumor effect against TNBC, and this antitumor effect was maximized by the combination of selumetinib with Aurora A and B inhibition.


Subject(s)
Aurora Kinase A/antagonists & inhibitors , Aurora Kinase B/antagonists & inhibitors , Indazoles/administration & dosage , Piperazines/administration & dosage , Protein Kinase Inhibitors/administration & dosage , Triple Negative Breast Neoplasms/drug therapy , Animals , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Apoptosis/drug effects , Aurora Kinase A/genetics , Aurora Kinase B/genetics , Benzimidazoles/administration & dosage , Cell Line, Tumor , Cell Proliferation/drug effects , Female , Humans , Mice , Triple Negative Breast Neoplasms/genetics , Triple Negative Breast Neoplasms/pathology , Xenograft Model Antitumor Assays
10.
J Cancer ; 6(4): 310-8, 2015.
Article in English | MEDLINE | ID: mdl-25767600

ABSTRACT

The purpose of this study was to determine the association between body mass index (BMI) measurements (baseline BMI and changes in BMI during neoadjuvant systemic treatment [NST]) and clinical efficacy (pathologic complete response [pCR] rate and survival outcomes) in locally advanced breast cancer (LABC). We hypothesized that high baseline BMI and increases in BMI during NST are associated with lower pCR rates and poorer clinical outcomes in LABC. We retrospectively reviewed the medical records of 1002 patients, 204 with primary inflammatory breast cancer (IBC) and 798 with stage III non-IBC, who underwent standard NST and definitive surgery between November 1, 2006, and December 31, 2012. The median follow-up time for the survivors was 19.6 months (0.4 - 67.8 months). The pCR rates of patients whose BMI increased or decreased were 23.2% and 18.1%, respectively, (p=0.048). The unadjusted overall survival (OS) was significantly better in the group with increased BMI (p=0.006). However, increased BMI was not an independent predictor of pCR and clinical outcomes (recurrence-free survival and OS) after adjusting for other clinical variables. In subset analyses, increased BMI as a continuous variable was an independent predictor of higher pCR rates in the normal BMI/underweight group (odds ratio [OR]=1.35, 95% confidence interval [CI]: 1.06-0.71, p=0.015). Increased BMI (BMI change ≥0 vs. <0) was also an independent predictor of pCR (OR=1.65, 95% CI: 1.00-2.72, p=0.049) in the postmenopausal group. Our results show that increasing BMI shows improved clinical outcome in terms of better pCR rates in normal BMI/underweight group and in the postmenopausal group. These results contradict previously reported findings on the association between high BMI and poor clinical efficacy regarding pCR rate and survival outcomes in early-stage breast cancer. Thus, the role of BMI in breast cancer may depend on patients' clinical characteristics such as advanced stage.

11.
Clin Breast Cancer ; 15(1): 37-42, 2015 Feb.
Article in English | MEDLINE | ID: mdl-25258308

ABSTRACT

BACKGROUND: Inflammatory breast cancer is a rare and aggressive presentation of breast cancer. Bone is a common metastatic site in breast cancer, and bone-only metastatic disease is clinically considered to have a better prognosis than visceral metastasis. However, bone-only metastasis in IBC (bone-only IBC) has not been compared with bone-only metastasis in non-IBC (bone-only non-IBC) in terms of clinical features and outcome. Because of the intrinsically aggressive nature of IBC, we hypothesized that bone-only IBC has a poorer prognosis than does bone-only non-IBC. PATIENTS AND METHODS: We retrospectively identified patients with stage III primary diagnosed breast cancer who, between January 1997 and December 2012, had a first recurrence located only in the bone. Among the 197 patients that we defined as a study cohort, 50 patients had IBC and 147 patients had non-IBC. Progression-free survival (PFS) and overall survival (OS) from the date of recurrence were estimated using the Kaplan-Meier method, and patient characteristic groups were compared using the log-rank test. RESULTS: OS did not differ significantly between the 2 groups (P = .2467), but a shorter PFS was seen in patients with bone-only IBC than in patients with bone-only non-IBC (P = .0357). Among patients with estrogen receptor (ER)-positive disease, a much shorter PFS was seen in bone-only IBC than in bone-only non-IBC (P = .0159). CONCLUSION: Bone-only IBC has a poorer prognosis than does bone-only non-IBC, particularly in those with ER-positive tumors. We might need to consider more aggressive intervention (e.g., chemotherapy) for IBC patients with ER-positive bone-only metastatic disease.


Subject(s)
Bone Neoplasms/secondary , Breast Neoplasms/diagnosis , Breast Neoplasms/pathology , Inflammatory Breast Neoplasms/diagnosis , Inflammatory Breast Neoplasms/pathology , Adult , Aged , Aged, 80 and over , Bone Neoplasms/diagnosis , Bone Neoplasms/mortality , Breast Neoplasms/mortality , Female , Humans , Inflammatory Breast Neoplasms/mortality , Middle Aged , Neoplasm Metastasis , Prognosis , Retrospective Studies , Survival Analysis
12.
Breast Cancer Res ; 15(6): R112, 2013 Nov 25.
Article in English | MEDLINE | ID: mdl-24274653

ABSTRACT

INTRODUCTION: Because of its high rate of metastasis, inflammatory breast cancer (IBC) has a poor prognosis compared with non-inflammatory types of breast cancer (non-IBC). In a recent study, Lehmann and colleagues identified seven subtypes of triple-negative breast cancer (TNBC). We hypothesized that the distribution of TNBC subtypes differs between TN-IBC and TN-non-IBC. We determined the subtypes and compared clinical outcomes by subtype in TN-IBC and TN-non-IBC patients. METHODS: We determined TNBC subtypes in a TNBC cohort from the World IBC Consortium for which IBC status was known (39 cases of TN-IBC; 49 cases of TN-non-IBC). We then determined the associations between TNBC subtypes and IBC status and compared clinical outcomes between TNBC subtypes. RESULTS: We found the seven subtypes exist in both TN-IBC and TN-non-IBC. We found no association between TNBC subtype and IBC status (P = 0.47). TNBC subtype did not predict recurrence-free survival. IBC status was not a significant predictor of recurrence-free or overall survival in the TNBC cohort. CONCLUSIONS: Our data show that, like TN-non-IBC, TN-IBC is a heterogeneous disease. Although clinical characteristics differ significantly between IBC and non-IBC, no unique IBC-specific TNBC subtypes were identified by mRNA gene-expression profiles of the tumor. Studies are needed to identify the subtle molecular or microenvironmental differences that contribute to the differing clinical behaviors between TN-IBC and TN-non-IBC.


Subject(s)
Inflammatory Breast Neoplasms/genetics , Inflammatory Breast Neoplasms/pathology , Triple Negative Breast Neoplasms/genetics , Triple Negative Breast Neoplasms/pathology , Adult , Aged , Cohort Studies , Female , Gene Expression Regulation, Neoplastic , Humans , Inflammatory Breast Neoplasms/metabolism , Inflammatory Breast Neoplasms/mortality , Middle Aged , Prognosis , Receptors, Androgen/genetics , Survival Analysis , Triple Negative Breast Neoplasms/metabolism , Triple Negative Breast Neoplasms/mortality
13.
Cancer Hallm ; 1(2-3): 59-66, 2013 Aug.
Article in English | MEDLINE | ID: mdl-25309822

ABSTRACT

A hallmark of metastatic cancer cells is their invasion through the basal membrane and endothelial layer, which requires a highly elastic cytoskeleton and nucleus. Therefore, cellular deformability can serve as a universal biophysical marker for detecting a tumor's propensity for invasion, migration, and metastasis. In this review, we define the importance of the biophysical features of cancer cells in tumor metastasis and summarize the state-of-the-art technology for the study of cell biomechanics. This review will serve as a brief introduction to the interdisciplinary character of cancer cell biophysics for cancer biologists, physicists, and engineers.

14.
Proc Natl Acad Sci U S A ; 109(46): 18707-12, 2012 Nov 13.
Article in English | MEDLINE | ID: mdl-23112172

ABSTRACT

Here we report a microfluidics method to enrich physically deformable cells by mechanical manipulation through artificial microbarriers. Driven by hydrodynamic forces, flexible cells or cells with high metastatic propensity change shape to pass through the microbarriers and exit the separation device, whereas stiff cells remain trapped. We demonstrate the separation of (i) a mixture of two breast cancer cell types (MDA-MB-436 and MCF-7) with distinct deformabilities and metastatic potentials, and (ii) a heterogeneous breast cancer cell line (SUM149), into enriched flexible and stiff subpopulations. We show that the flexible phenotype is associated with overexpression of multiple genes involved in cancer cell motility and metastasis, and greater mammosphere formation efficiency. Our observations support the relationship between tumor-initiating capacity and cell deformability, and demonstrate that tumor-initiating cells are less differentiated in terms of cell biomechanics.


Subject(s)
Cell Separation/instrumentation , Cell Separation/methods , Microfluidic Analytical Techniques , Neoplastic Stem Cells/cytology , Spheroids, Cellular/cytology , Cell Line, Tumor , Humans
15.
Int J Cancer ; 130(11): 2568-79, 2012 Jun 01.
Article in English | MEDLINE | ID: mdl-21717460

ABSTRACT

Triple-negative breast cancer [TNBC, which is negative for the estrogen receptor (ER), progesterone receptor, and human epidermal growth factor receptor 2] is a high-risk form of the disease without a specific therapy. DNA microarray and immunohistochemical analyses have shown that most TNBCs fall within the basal-like histological subset of breast cancers, which frequently exhibit inactivation of the retinoblastoma tumor suppressor (Rb) and upregulation of the cyclin-dependent kinase inhibitor p16(INK4a) (p16). However, downregulation of p16 expression has been observed in some basal-like breast cancer cell lines, suggesting that such cells can be divided into two groups according to Rb and p16 status. We now show that cells that are CD44(+) and CD24(-) , a phenotype associated with stem-like breast cancer cells, are more abundant in ER(-) /p16(-) breast cancer cell lines than in ER(-) /p16(+) lines. It was also found that p16 expression was downregulated in mammospheres from an ER-negative breast cancer cell line. Depletion of p16 by RNA interference in ER-negative breast cancer cells increased the percentage of CD44(+) /CD24(-) cells and increased the expression of mRNA of the ES-like genes Nanog, Oct4, and Sox2 through an Rb-independent pathway. Furthermore, such depletion of p16 reduced chemosensitivity. The loss of p16 expression may thus reduce the response of ER-negative breast cancer cells to chemotherapy by conferring cancer stem cell-like properties. Consistent with this conclusion, immunohistochemical analysis of the clinical samples suggests that low p16 expression in TNBC is associated with resistance to preoperative chemotherapy.


Subject(s)
Breast Neoplasms/drug therapy , Neoplasm Proteins/physiology , Adult , Aged , Apoptosis/drug effects , Breast Neoplasms/chemistry , Breast Neoplasms/pathology , CD24 Antigen/analysis , Cell Line, Tumor , Cyclin-Dependent Kinase Inhibitor p16 , Drug Resistance, Neoplasm , Female , Homeodomain Proteins/genetics , Humans , Hyaluronan Receptors/analysis , Middle Aged , Nanog Homeobox Protein , Neoplastic Stem Cells , Octamer Transcription Factor-3/genetics , Paclitaxel/pharmacology , Phosphorylation , Receptors, Estrogen/analysis , Retinoblastoma Protein/physiology , SOXB1 Transcription Factors/genetics , Smad3 Protein/metabolism
16.
Neoplasia ; 13(9): 784-91, 2011 Sep.
Article in English | MEDLINE | ID: mdl-21969812

ABSTRACT

Invasiveness, cellular atypia, and proliferation are hallmarks of malignant gliomas. To effectively target each of these characteristics, it is important to understand their sequence during tumorigenesis. However, because most gliomas are diagnosed at an advanced stage, the chronology of gliomagenesis milestones is not well understood. The aim of the present study was to determine the onset of these characteristics during tumor development. Brain tumor-initiating cells (BTICs) were established by overexpressing H-Ras(V12) in normal neural stem/progenitor cells isolated from the subventricular zone of adult mice harboring a homozygous deletion of the Ink4a/Arf locus. High-grade malignant brain tumors were then created by orthotopic implantation of 10(5) BTICs into the forebrain of 6-week-old wild-type mice. Micewere killed every week for 5 weeks, and tumors were assessed for cellular atypia, proliferation, hemorrhage, necrosis, and invasion. All mice developed highly invasive, hypervascular glioblastoma-like tumors. A 100% penetrance rate and a 4-week median survival were achieved. Tumor cell migration along fiber tracts started within days after implantation and was followed by perivascular infiltration of tumor cells with marked recruitment of reactive host cells. Next, cellular atypia became prominent. Finally, mass proliferation and necrosis were observed in the last stage of the disease. Video monitoring of BTICs in live brain slices confirmed the early onset of migration, as well as the main cell migration patterns. Our results showed that perivascular and intraparenchymal tumor cell migration precede tumor mass formation in the adult brain, suggesting the need for an early and sustained anti-invasion therapy.


Subject(s)
Brain Neoplasms/pathology , Cell Movement , Glioblastoma/pathology , Animals , Cell Line, Tumor , Cell Proliferation , Cyclin-Dependent Kinase Inhibitor p16/genetics , Mice , Mice, Inbred C57BL , Mice, Knockout , Necrosis , Neoplasm Invasiveness/pathology , Neoplasm Transplantation , Neural Stem Cells , Proto-Oncogene Proteins p21(ras)/biosynthesis , Tumor Suppressor Protein p14ARF/genetics
17.
Cancer Cell ; 19(3): 387-400, 2011 Mar 08.
Article in English | MEDLINE | ID: mdl-21397861

ABSTRACT

CD44 is an adhesion molecule expressed in cancer stem-like cells. Here, we show that a CD44 variant (CD44v) interacts with xCT, a glutamate-cystine transporter, and controls the intracellular level of reduced glutathione (GSH). Human gastrointestinal cancer cells with a high level of CD44 expression showed an enhanced capacity for GSH synthesis and defense against reactive oxygen species (ROS). Ablation of CD44 induced loss of xCT from the cell surface and suppressed tumor growth in a transgenic mouse model of gastric cancer. It also induced activation of p38(MAPK), a downstream target of ROS, and expression of the gene for the cell cycle inhibitor p21(CIP1/WAF1). These findings establish a function for CD44v in regulation of ROS defense and tumor growth.


Subject(s)
Amino Acid Transport System y+/metabolism , Cell Proliferation , Hyaluronan Receptors/metabolism , Stomach Neoplasms/metabolism , Amino Acid Transport System y+/genetics , Animals , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cell Line, Tumor , Female , Gene Expression Profiling , HCT116 Cells , HEK293 Cells , HT29 Cells , Humans , Hyaluronan Receptors/genetics , Male , Mice , Mice, Knockout , Mice, Nude , Mice, Transgenic , Oxidation-Reduction , Protein Isoforms/genetics , Protein Isoforms/metabolism , Protein Stability , Protein Subunits/genetics , Protein Subunits/metabolism , RNA Interference , Stomach Neoplasms/drug therapy , Stomach Neoplasms/pathology , Tumor Burden/genetics , Xenograft Model Antitumor Assays
18.
Oncol Lett ; 2(2): 303-308, 2011 Mar.
Article in English | MEDLINE | ID: mdl-22866081

ABSTRACT

Trastuzumab has shown significant clinical benefits in patients with operable and metastatic HER2-positive breast cancer. However, the biological mechanism of the additional effect of trastuzumab administered in combination with conventional chemotherapy is poorly understood. We performed a retrospective analysis of 55 patients with HER2-positive breast cancer treated with anthracycline and taxane (chemotherapy alone; CT), or trastuzumab in combination with taxane-based chemotherapy (CT+T) for neoadjuvant chemotherapy. We determined the therapeutic efficacies [clinical (CR) and pathological complete responses (pCR)] and changes in the proportion of positive cells for each biomarker pre- to post-neoadjuvant chemotherapy for each treatment regimen. Clinical-CR and quasi-pCR rates defined as the absence of invasive tumors or only a few remaining invasive tumor cells were 6.9 and 31.0% in the CT group and 46.2 and 65.4% in the CT+T group, respectively. In the CT group, the proportion of estrogen receptor (ER)-/progesterone receptor (PgR)-positive cells decreased significantly following treatment (ER, 73.5 vs. 50.9%; P=0.02). Changes in the proportion of ER-/PgR-positive cells were not noted in the CT+T group (ER, 81.9 vs. 80.3%; P=0.61), although a relatively greater decrease in the proportion of Ki-67-positive cells was found in the CT+T group than that in the CT group (-26.5 vs. -13.7%). These findings indicate that CT+T inhibits ER-negative and Ki-67-positive breast cancer cells. In conclusion, trastuzumab sensitized ER-negative proliferative cells to cytotoxic chemotherapy. This finding may indicate an additional clinical effect of trastuzumab when administered in combination with conventional chemotherapy as neoadjuvant chemotherapy for HER2-positive breast cancer.

19.
Breast Cancer ; 17(2): 80-5, 2010 Apr.
Article in English | MEDLINE | ID: mdl-19806428

ABSTRACT

Since the initial discovery of leukemia stem cells nearly a decade ago, a great deal of cancer research has focused on the identification of cancer stem cells (CSCs) in many types of solid tumors, including breast cancer. Through analysis of cell surface markers and xenotransplant models, a subpopulation of putative human breast cancer stem cells (BCSCs) that is CD24-negative/CD44-positive (CD24(-)/CD44+) and bears high aldehyde dehydrogenase 1 activity has been isolated in clinical samples of breast cancer tissues. Human BCSCs are considered to be derived from basal cells that reside in the basal membranes of alveolar units in human adult mammary glands. Furthermore, BCSCs have been shown to express higher levels of oxidative stress-responsive genes, which could confer part of their ability to resist anti-cancer therapy, than non-CSCs. The emerging picture of the biological properties of BCSCs would contribute for devising innovative therapies for breast cancer, targeting the intrinsic and extrinsic factors that maintain the BCSCs.


Subject(s)
Breast Neoplasms/pathology , Neoplastic Stem Cells/pathology , Female , Humans
20.
Cancer Sci ; 101(3): 673-8, 2010 Mar.
Article in English | MEDLINE | ID: mdl-20028388

ABSTRACT

Similar to normal tissue stem cells, cancer stem cells (CSCs) are thought to be quiescent or slow-cycling and, thereby, insensitive to chemo- and radiotherapies. CD44, a cell surface component that interacts with the extracellular matrix, has been found to be highly expressed in CSCs of several solid tumors. However, the relevancy between CD44(+) cells and slow-cycling cells and the underlying mechanisms for the emergence of CD44(+) CSCs during tumorigenesis have not been elucidated. Here we show that a gastric gland residing at the squamo-columnar junction (SCJ) in normal mouse stomach contains CD44(+) stem cell-like slow-cycling cells and that this characteristic CD44(+) gland was expanded by prostaglandin E2 (PGE(2)) and Wnt signaling in K19-Wnt1/C2mE mouse, a genetic mouse model for gastric tumorigenesis. The analysis of three transgenic mouse lines, K19-Wnt1, K19-C2mE and K19-Wnt1/C2mE, revealed that the expansion of CD44(+) SCJ cells is triggered by PGE(2)-mediated signaling and is prominently enhanced by the addition of Wnt activation. Furthermore, each expanded CD44(+) gland in gastric tumor of K19-Wnt1/C2mE mouse contains a few BrdU label-retaining quiescent or slow-cycling cells, suggesting that the CD44(+) SCJ cells in normal mouse are candidates for the cell-of-origin of gastric CSCs. These observations suggest that PGE(2)-mediated inflammatory signaling and Wnt signaling cooperatively trigger the expansion of CD44(+) slow-cycling stem-like cells in SCJ, leading to development of lethal gastric tumors in mice.


Subject(s)
Dinoprostone/physiology , Hyaluronan Receptors/physiology , Stomach Neoplasms/etiology , Wnt1 Protein/physiology , Animals , Cyclooxygenase 2/physiology , Female , Hyaluronan Receptors/analysis , Intramolecular Oxidoreductases/physiology , Mice , Mice, Transgenic , Prostaglandin-E Synthases , Rats , Rats, Inbred F344
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