Overexpression of CD44 accompanies acquired tamoxifen resistance in MCF7 cells and augments their sensitivity to the stromal factors, heregulin and hyaluronan

Background: Acquired resistance to endocrine therapy in breast cancer is a significant problem with relapse being associated with local and/or regional recurrence and frequent distant metastases. Breast cancer cell models reveal that endocrine resistance is accompanied by a gain in aggressive behaviour driven in part through altered growth factor receptor signalling, particularly involving erbB family receptors. Recently we identified that CD44, a transmembrane cell adhesion receptor known to interact with growth factor receptors, is upregulated in tamoxifen-resistant (TamR) MCF7 breast cancer cells. The purpose of this study was to explore the consequences of CD44 upregulation in an MCF7 cell model of acquired tamoxifen resistance, specifically with respect to the hypothesis that CD44 may influence erbB activity to promote an adverse phenotype. Methods: CD44 expression in MCF7 and TamR cells was assessed by RT-PCR, Western blotting and immunocytochemistry. Immunofluorescence and immunoprecipitation studies revealed CD44-erbB associations. TamR cells (± siRNA-mediated CD44 suppression) or MCF7 cells (± transfection with the CD44 gene) were treated with the CD44 ligand, hyaluronon (HA), or heregulin and their in vitro growth (MTT), migration (Boyden chamber and wound healing) and invasion (Matrigel transwell migration) determined. erbB signalling was assessed using Western blotting. The effect of HA on erbB family dimerisation in TamR cells was determined by immunoprecipitation in the presence or absence of CD44 siRNA. Results: TamR cells overexpressed CD44 where it was seen to associate with erbB2 at the cell surface. siRNA-mediated suppression of CD44 in TamR cells significantly attenuated their response to heregulin, inhibiting heregulin-induced cell migration and invasion. Furthermore, TamR cells exhibited enhanced sensitivity to HA, with HA treatment resulting in modulation of erbB dimerisation, ligand-independent activation of erbB2 and EGFR and induction of cell migration. Overexpression of CD44 in MCF7 cells, which lack endogenous CD44, generated an HA-sensitive phenotype, with HA-stimulation promoting erbB/EGFR activation and migration. Conclusions: These data suggest an important role for CD44 in the context of tamoxifen-resistance where it may augment cellular response to erbB ligands and HA, factors that are reported to be present within the tumour microenvironment in vivo. Thus CD44 may present an important determinant of breast cancer progression in the setting of endocrine resistance

Molecule-Based Magnets: Ferro- and Antiferromagnetic Interactions in Nickel(II) Cyclohexasiloxanolate Sandwich Complexes

Ferromagnetic exchange-coupling interactions mediated by siloxanolate ligands have been detected in the two nickel(II) nanoscale clusters Na2[(PhSiO2)6Na4Ni4(OH)2(O2SiPh)6]. 16Bu(n)OH (1) and Na2[(PhSiO2)6Ni6(O2SiPh)6Cl].12CH3OH. H2O (2), which qualify as interesting precursors for new molecule-based magnetic materials. Complex 1 has an S = 4 spin ground state, whereas complex 2 has an S = 0 spin ground state. due to the presence of additional antiferromagnetic interactions through the encapsulated mu(6)-chloride ion

SILOXANE CLUSTERS OF HIGHER VALENCE TRANSITION-METALS - REDOX PROPERTIES

Cyclic voltammetric behaviour of polymetallic complexes of hexaphenylcyclohexasiloxane-hexaol with Ni, Mn and dodecaphenyl-cyclododecasiloxane-dodecaol with Cu was studied. The complexes react electrochemically as a unit assembly of the complexed metals

Heterobimetallic cyclosiloxanolate sandwich clusters: Na{[η6-cyclo(PhSiO2)6]2[Fe(OR)]2Ni4(μ6-Cl)} (R = H, Me)

The heterobimetallic cyclosiloxanolate sandwich clusters Na{[η6-cyclo(PhSiO2)6]2[Fe(OR)]2Ni4(μ6-Cl)} (R = H, Me) (1) were prepd. from Na2{[(PhSiO2)6]2Na4Ni4(OH)2} as solvates. The new clusters 1 were characterized by spectra (UV-visible, IR, 1H-NMR), cyclic voltammetry, cond., magnetic susceptibility, and single-crystal x-ray diffraction for 1·10MeOH (R = Me)

New Cyclosiloxanolate Cluster Complexes of Transition Metals

New cyclosiloxanolate transition metal cluster complex derivs. were prepd. PhSiO2K reacted with NiX2 (X2 = Cl2 or acac) to give K2{[η6-(PhSiO2)6]2[μ3-(OH)]2Ni4K4}, a mixed Group 1-group 10 metal complex. PhSiO2Na reacted with Ni(NH3)6I2 to give Na{[η6-(PhSiO2)6]2Ni6(μ6-I)} as the 1st example of encapsulated I- ion in siloxanolate complexes. The macrocyclic Na4{[η12-(PhSiO2)12]Cu4} complex reacted with η6-(1,3,5-C7H8)Cr(CO)3 to give the heterobimetallic adduct Na4{[η12-(PhSiO2)12]Cu4}[Cr(CO)3]3 as one of the rare examples of heterobimetallic complexes with different oxidn. nos. of the metals. The Cu deriv. {[η6-(PhSiO2)6]2Cu6(BuOH)5} reacted in MeOH/CHCl3 (1:6) with Et4NCN to give hexanuclear {[η6-(PhSiO2)6]2Cu6(η2-C3H5N2O2)2}, contg. 2-amino-2-oxoethanimidic acid Me ester monoanion ligands, product of an unexpected C-C coupling reaction. This latter complex was characterized also by x-ray diffraction crystal and mol. structure detn

Bimetallic Cyclooligosiloxanolate Complexes of Copper and Nickel

The bimetallic cyclosiloxanolate cluster complexes Na[(PhSiO2)6Cu4Ni2(μ6-Cl)(PhSiO2)6] (1) and Na[(PhSiO2)6Cu3Ni3(μ6-Cl)(PhSiO2)6] (2) were prepd. by Na+ and Ni2+ ion exchange from in situ generated Na2{[(PhSiO2)6]2Na4Ni4(OH)2}. Complexes 1 and 2 were characterized by anal., spectroscopic and electrochem. methods as well as complex 2 by single-crystal x-ray diffraction (2·7DMSO·H2O: orthorhombic, space group P212121, R = 0.076). The x-ray structure shows a sandwich-type array comprising two superimposed cyclosiloxanolate rings and an M6Cl unit in between. For the 1st time the regioselectivity of the metal ion exchange could be deduced from the x-ray structural parameters

Energy level spectroscopy of InSb quantum wells using quantum-well LED emission

We have investigated the low-temperature optical properties of InSb quantum-well (QW) light-emitting diodes, with different barrier compositions, as a function of well width. Three devices were studied: QW1 had a 20 nm undoped InSb quantum well with a barrier composition of Al0.143In0.857Sb, QW2 had a 40 nm undoped InSb well with a barrier composition of Al0.077In0.923Sb, and QW3 had a 100 nm undoped InSb well with a barrier composition of Al0.025In0.975Sb. For QW1, the signature of two transitions (CB1-HH1 and CB1-HH2) can be seen in the measured spectrum, whereas for QW2 and QW3 the signature of a large number of transitions is present in the measured spectra. In particular transitions to HH2 can be seen, the first time this has been observed in AlInSb/InSb heterostructures. To identify the transitions that contribute to the measured spectra, the spectra have been simulated using an eight-band k.p calculation of the band structure together with a first-order time-dependent perturbation method (Fermi golden rule) calculation of spectral emittance, taking into account broadening. In general there is good agreement between the measured and simulated spectra. For QW2 we attribute the main peak in the experimental spectrum to the CB2-HH1 transition, which has the highest overall contribution to the emission spectrum of QW2 compared with all the other interband transitions. This transition normally falls into the category of "forbidden transitions," and in order to understand this behavior we have investigated the momentum matrix elements, which determine the selection rules of the problem