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Query: UMLS:C0006142 (breast cancer)
 160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Evaluation of: Daniels MJ, Wang Y, Lee M, Venkitaraman AR: Abnormal cytokinesis in cells deficient in the breast cancer susceptibility protein BRCA2. Science 306, 876-879 (2004). Cytokinesis is the division of the cytoplasm of a parent cell into daughter cells after nuclear division. Cytokinesis failure is often accompanied by the generation of cells with an unstable tetraploidy content, which predisposes the cells to develop aneuploidy and malignancies. A recent study by Venkitaraman's group demonstrates that BRCA2, a breast cancer susceptibility gene product, also functions in mediating normal cytokinesis. Similar to the subcellular localization of Aurora kinase, BRCA2 is present at the cleavage furrow and the midbody during late mitosis. Deficiency in BRCA2 function results in cytokinesis failure, which is associated with abnormal localization of myosin II, a key protein essential for the formation of the cleavage furrow. This study is of significance as it shows for the first time that BRCA2 has a function in controlling mitotic exit, deregulation of which contributes to gross genomic instabilities in daughter cells.
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PMID:BRCA2 in mitotic exit: a new role in regulating genomic stability. 1655 71

Initial stages of tumor cell metastasis involve an epithelial-mesenchyme transition that involves activation of amoeboid migration and loss of cell-cell adhesion. The actomyosin cytoskeleton has fundamental but poorly understood roles in these events. Myosin II, an abundant force-producing protein, has roles in cell body translocation and retraction of the posterior of the cell during migration. Recent studies have suggested that this protein may also have roles in leading edge protrusive events. The metastasis-promoting protein metastasin-1, a regulator of myosin II assembly, colocalizes with myosin IIA at the leading edge of cancer cells, suggesting direct roles for myosin II in metastatic behavior. We have assessed the roles of specific myosin II isoforms during lamellar spreading of MDA-MB-231 breast cancer cells on extracellular matrix. We find that the two major myosin II isoforms IIA and IIB are both expressed in these cells, and both are recruited dramatically to the lamellar margin during active spreading on fibronectin. There is also a transient increase in regulatory light chain phosphorylation that correlates the recruitment of myosin IIA and myosin IIB into this spreading margin. Pharmacologic inhibition of myosin II or myosin light chain kinase dramatically reduced spreading. Depletion of myosin IIA via small interfering RNA impaired migration but enhanced lamellar spreading, whereas depletion of myosin IIB impaired not only migration but also impaired initial rates of lamellar spreading. These results indicate that both isoforms are critical for the mechanics of cell migration, with myosin IIB seeming to have a preferential role in the mechanics of lamellar protrusion.
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PMID:Distinct roles of nonmuscle myosin II isoforms in the regulation of MDA-MB-231 breast cancer cell spreading and migration. 1665 25

In mammalian nonmuscle cells, the mechanisms controlling the localized formation of myosin-II filaments are not well defined. To investigate the mechanisms mediating filament assembly and disassembly during generalized motility and chemotaxis, we examined the EGF-dependent phosphorylation of the myosin-IIA heavy chain in human breast cancer cells. EGF stimulation of MDA-MB-231 cells resulted in transient increases in both the assembly and phosphorylation of the myosin-IIA heavy chains. In EGF-stimulated cells, the myosin-IIA heavy chain is phosphorylated on the casein kinase 2 site (S1943). Cells expressing green fluorescent protein-myosin-IIA heavy-chain S1943E and S1943D mutants displayed increased migration into a wound and enhanced EGF-stimulated lamellipod extension compared with cells expressing wild-type myosin-IIA. In contrast, cells expressing the S1943A mutant exhibited reduced migration and lamellipod extension. These observations support a direct role for myosin-IIA heavy-chain phosphorylation in mediating motility and chemotaxis.
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PMID:Myosin-IIA heavy-chain phosphorylation regulates the motility of MDA-MB-231 carcinoma cells. 1756 56

Lymphovascular invasion is an adverse prognostic factor in breast cancer. The lymphatic endothelial marker D2-40 has been shown to improve accuracy in detecting lymphovascular invasion. In addition to marking lymphatic endothelium, D2-40 has been cursorily noted to react with breast myoepithelium. The extent of this expression and the potential for misinterpreting in situ carcinoma as lymphovascular invasion because of D2-40-positive myoepithelium have not been formally addressed. The aim of this study was to determine the scope of breast myoepithelial expression of D2-40 and to identify problematic patterns of expression by in situ carcinoma that could be confused with lymphovascular invasion. We evaluated the distribution and intensity of D2-40 immunohistochemical expression in breast myoepithelium in normal breast (n = 50), proliferative fibrocystic changes (n = 10), ductal carcinoma in situ (n = 35), and lobular carcinoma in situ (n = 5). All cases of normal breast exhibited a variable degree of D2-40 expression by myoepithelium. The distribution was patchy and the intensity was less than that of the adjacent lymphatic endothelium. Larger ducts were more often positive than terminal ducts and lobules. D2-40 marked 77% of ductal carcinoma in situ cases and all lobular carcinoma in situ cases to a variable degree. Only a minority of involved ducts were reactive in each positive case; the intensity was weak to moderate. Although the tumor growth pattern generally enabled distinction of ductal carcinoma in situ from lymphovascular invasion, D2-40 myoepithelial expression in small ducts completely filled by solid-pattern ductal carcinoma in situ mimicked the pattern expected for lymphovascular invasion. Morphology of these myoepithelial cells was not diagnostically helpful as their compressed, stretched-out shape mimicked that of endothelium. Myoepithelial markers (p63 and smooth muscle myosin) confirmed each diagnosis of ductal carcinoma in situ. Lobular carcinoma in situ posed similar problems. The interpretation of D2-40 in the breast requires awareness that myoepithelium may also be immunoreactive. Solid-pattern ductal carcinoma in situ and lobular carcinoma in situ may be misinterpreted as lymphovascular invasion. We recommend that myoepithelial markers be used in conjunction with D2-40 to distinguish solid intralymphatic tumor emboli from solid pattern in situ carcinoma.
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PMID:D2-40 expression by breast myoepithelium: potential pitfalls in distinguishing intralymphatic carcinoma from in situ carcinoma. 1820 95

Regressive changes (RC) have been described in malignant melanoma, carcinomas of the prostate and cervix. The presence of RC in these neoplasms may signify some degree of host response to tumor and seems to be a sign of poor prognosis for some neoplasms. RC in breast cancer is vaguely defined in the older literature. We have observed periodically similar RC in a subset of high-grade ductal carcinoma in situ (HGDCIS) in breast specimens. The aim of our study is to demonstrate how to recognize RC in the diagnostic setting and an attempt to understand the biologic behavior in this subset of HGDCIS cases. Fifty-nine cases of HG-DCIS (35 cases with RC and 24 cases without RC) were included. We defined RC in our study as demonstrating thick periductal fibrosis, dense lymphocytic infiltrate, and a thin rim of intact neoplastic cells. A short panel of immunomarkers to study this entity included myoepithelial markers. Reduced expression of myoepithelial markers (p63 and smooth muscle heavy chain myosin) were seen more frequently in the HGDCIS group with RC than without RC cases. Invasion as well as metastatic disease was seen in association with HGDCIS with RC nearly 4 times as often. It is also critically important to recognize HGDCIS-RC for diagnostic purposes, as the differential diagnosis of RC includes, benign associations such as papilloma, fibrocystic changes and periductal mastitis. HGDCIS-RC may also be a sign of an aggressive phenotype than other HGDCIS subtypes. Further outcome studies are necessary to determine if it has a clinical impact akin to other tumors with RC.
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PMID:Characterization of high-grade ductal carcinoma in situ with and without regressive changes: diagnostic and biologic implications. 1940 54

The small guanine triphosphatase (GTPase) proteins RhoA and RhoC are essential for tumor invasion and/or metastasis in breast carcinomas. However, it is poorly understood how RhoA and RhoC are activated in breast cancer cells. Here we describe the role of myosin-interacting guanine nucleotide exchange factor (Myo-GEF) in regulating RhoA and RhoC activation as well as cell polarity and invasion in an invasive breast cancer cell line MDA-MB-231. RNA-interference (RNAi)-mediated depletion of MyoGEF in MDA-MB-231 cells not only suppresses the activation of RhoA and RhoC, but also decreases cell polarity and invasion activity. The dominant-negative mutants of RhoA and RhoC, but not Rac1 and Cdc42, dramatically decrease actin polymerization induced by MyoGEF. In addition, MyoGEF co-localizes with nonmuscle myosin IIA (NMIIA) to the front of migrating cells, and depletion of NMIIA by RNAi disrupts the polarized localization of MyoGEF at the cell leading edge, suggesting a role for NMIIA in regulating MyoGEF localization and function. Moreover, MyoGEFprotein levels significantly increase in infiltrating ductal carcinomas as well as in invasive breast cancer cell lines. Taken together, our results suggest that MyoGEF cooperates with NMIIA to regulate the polarity and invasion activity of breast cancer cells through activation of RhoA and RhoC.
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PMID:Myosin-interacting guanine exchange factor (MyoGEF) regulates the invasion activity of MDA-MB-231 breast cancer cells through activation of RhoA and RhoC. 1942 Nov 44

Rho-associated kinase (ROCK) signaling plays a fundamental role in regulating cell morphology, adhesion, and motility. Aberrant expression of ROCK is related to tumor metastases and poor clinical outcome. Here, we show that ROCK expression is increased in metastatic human mammary tumors and breast cancer cell lines compared with nonmetastatic tumors and cell lines. Overexpression of ROCK confers a metastatic phenotype on the nonmetastatic MCF-7 cell line. Inhibition of ROCK activity, by either a specific ROCK inhibitor (Y27632) or ROCK-targeted small interfering RNAs, reduces cell migration and proliferation in vitro and metastasis to bone in vivo using a novel "human breast cancer metastasis to human bone" mouse model. Expression of the c-Myc-regulated miR-17-92 cluster is shown to be elevated in metastatic breast cancer cells compared with nonmetastatic cells and diminished by Y27632 treatment. Furthermore, blockade of miR-17 is shown to decrease breast cancer cell invasion/migration in vitro and metastasis in vivo. Together, these findings suggest that augmented ROCK signaling contributes to breast cancer metastasis. The effects of ROCK on tumor cell invasion/motility and growth may derive from regulating cytoskeletal actin-myosin contraction and modulating the c-Myc pathway, including c-Myc-dependent microRNAs. Inhibition of ROCK or the pathway it stimulates, therefore, may represent a novel approach for treatment of breast cancer metastases.
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PMID:Inhibition of rho-associated kinase signaling prevents breast cancer metastasis to human bone. 1988 17

The transient and localized signaling events between invasive breast cancer cells and the underlying endothelial cells have remained poorly characterized. We report a novel approach integrating vascular engineering with three-dimensional time-lapse fluorescence resonance energy transfer (FRET) imaging to dissect how endothelial myosin light chain kinase (MLCK) is modulated during tumor intravasation. We show that tumor transendothelial migration occurs via both paracellular (i.e. through cell-cell junctions) and transcellular (i.e. through individual endothelial cells) routes. Endothelial MLCK is activated at the invasion site, leading to regional diphosphorylation of myosin-II regulatory light chain (RLC) and myosin contraction. Blocking endothelial RLC diphosphorylation blunts tumor transcellular, but not paracellular, invasion. Our results implicate an important role for endothelial myosin-II function in tumor intravasation.
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PMID:Myosin light chain kinase mediates transcellular intravasation of breast cancer cells through the underlying endothelial cells: a three-dimensional FRET study. 2006 98

Estrogen receptor alpha (ERalpha) is a modular protein of the steroid/nuclear receptor family of transcriptional regulators that upon binding to the hormone undergoes structural changes, resulting in its nuclear translocation and docking to specific chromatin sites. In the nucleus, ERalpha assembles in multiprotein complexes that act as final effectors of estrogen signaling to the genome through chromatin remodeling and epigenetic modifications, leading to dynamic and coordinated regulation of hormone-responsive genes. Identification of the molecular partners of ERalpha and understanding their combinatory interactions within functional complexes is a prerequisite to define the molecular basis of estrogen control of cell functions. To this end, affinity purification was applied to map and characterize the ERalpha interactome in hormone-responsive human breast cancer cell nuclei. MCF-7 cell clones expressing human ERalpha fused to a tandem affinity purification tag were generated and used to purify native nuclear ER-containing complexes by IgG-Sepharose affinity chromatography and glycerol gradient centrifugation. Purified complexes were analyzed by two-dimensional DIGE and mass spectrometry, leading to the identification of a ligand-dependent multiprotein complex comprising beta-actin, myosins, and several proteins involved in actin filament organization and dynamics and/or known to participate in actin-mediated regulation of gene transcription, chromatin dynamics, and ribosome biogenesis. Time course analyses indicated that complexes containing ERalpha and actin are assembled in the nucleus early after receptor activation by ligands, and gene knockdown experiments showed that gelsolin and the nuclear isoform of myosin 1c are key determinants for assembly and/or stability of these complexes. Based on these results, we propose that the actin network plays a role in nuclear ERalpha actions in breast cancer cells, including coordinated regulation of target gene activity, spatial and functional reorganization of chromatin, and ribosome biogenesis.
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PMID:Identification of a hormone-regulated dynamic nuclear actin network associated with estrogen receptor alpha in human breast cancer cell nuclei. 2030 91

Caveolin-1 and caveolae are often lost in cancer. We found that levels of caveolin-1 and polymerase I and transcript release factor (PTRF)/cavin-1 correlated closely in a panel of cancer and normal cells. Caveolin-1 reexpression in cancer cells lacking both proteins induced formation of long membrane tubules rarely seen in normal cells. PTRF/cavin-1 inhibited tubule formation when coexpressed with caveolin-1 in these cells, whereas suppression of PTRF/cavin-1 expression in cells that normally expressed both genes stimulated tubule formation by endogenous caveolin-1. Caveolin-1 tubules shared several features with previously described Rab8 tubules. Coexpressed Rab8 and caveolin-1 labeled the same tubules (as did EHD proteins), and synergized to promote tubule formation, whereas a dominant-interfering Rab8 mutant inhibited caveolin-1 tubule formation. Both overexpression and inhibition of dynamin-2 reduced the abundance of caveolin-1 tubules. Caveolin-1 reexpression in SK-BR-3 breast cancer cells also induced formation of short membrane tubules close to cortical actin filaments, which required actin filaments but not microtubules. Actomyosin-induced tension destabilized both long and short tubules; they often snapped and resolved to small vesicles. Actin filament depolymerization or myosin II inhibition reduced tension and stabilized tubules. These data demonstrate a new function for PTRF/cavin-1, a new functional interaction between caveolin-1 and Rab8 and that actomyosin interactions can induce tension on caveolin-1-containing membranes.
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PMID:Caveolin-1 induces formation of membrane tubules that sense actomyosin tension and are inhibited by polymerase I and transcript release factor/cavin-1. 2042 76


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