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

被引:60
作者
Hiscox, Stephen [1 ]
Baruha, Bedanta
Smith, Chris [1 ]
Bellerby, Rebecca [2 ]
Goddard, Lindy [1 ]
Jordan, Nicola [1 ]
Poghosyan, Zaruhi [3 ]
Nicholson, Robert I. [1 ]
Barrett-Lee, Peter
Gee, Julia [1 ]
机构
[1] Cardiff Univ, Welsh Sch Pharm, Cardiff, Wales
[2] Cardiff Univ, Sch Biosci, Cardiff, Wales
[3] Cardiff Univ, Sch Med, Cardiff, Wales
关键词
Tamoxifen-resistance; CD44; erbB; Hyaluronan; Heregulin; BREAST-CANCER CELLS; C-MET; DRUG-RESISTANCE; IN-VITRO; GROWTH; TUMOR; RECEPTOR; EXPRESSION; LOCALIZATION; SURVIVAL;
D O I
10.1186/1471-2407-12-458
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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.
引用
收藏
页数:14
相关论文
共 62 条
[1]  
Abe O, 2005, LANCET, V366, P2087, DOI 10.1016/s0140-6736(05)66544-0
[2]   Role of CD44s and CD44v6 on human breast cancer cell adhesion, migration, and invasion [J].
Afify, Alaa ;
Purnell, Phillip ;
Nguyen, Laura .
EXPERIMENTAL AND MOLECULAR PATHOLOGY, 2009, 86 (02) :95-100
[3]   Expression of CD44s and CD44v6 in lung cancer and their correlation with prognostic factors [J].
Afify, Alaa M. ;
Tate, Stacey ;
Durbin-Johnson, Blythe ;
Rocke, David M. ;
Konia, Thomas .
INTERNATIONAL JOURNAL OF BIOLOGICAL MARKERS, 2011, 26 (01) :50-57
[4]   A CD44-/CD24+ phenotype is a poor prognostic marker in early invasive breast cancer [J].
Ahmed, Mohamed A. H. ;
Aleskandarany, Mohammed A. ;
Rakha, Emad A. ;
Moustafa, Radwa Z. A. ;
Benhasouna, Ahmed ;
Nolan, Christopher ;
Green, Andrew R. ;
Ilyas, Mohammad ;
Ellis, Ian O. .
BREAST CANCER RESEARCH AND TREATMENT, 2012, 133 (03) :979-995
[5]   ErbB380 kDa, a nuclear variant of the ErbB3 receptor, binds to the Cyclin D1 promoter to activate cell proliferation but is negatively controlled by p14ARF [J].
Andrique, Laetitia ;
Fauvin, Dominique ;
El Maassarani, Mahmoud ;
Colasson, Helene ;
Vannier, Brigitte ;
Seite, Paule .
CELLULAR SIGNALLING, 2012, 24 (05) :1074-1085
[6]   Hyaluronan in peritumoral stroma and malignant cells associates with breast cancer spreading and predicts survival [J].
Auvinen, P ;
Tammi, R ;
Parkkinen, J ;
Tammi, M ;
Ågren, U ;
Johansson, R ;
Hirvikoski, P ;
Eskelinen, M ;
Kosma, VM .
AMERICAN JOURNAL OF PATHOLOGY, 2000, 156 (02) :529-536
[7]   Hyaluronan-mediated CD44 activation of RhoGTPase signaling and cytoskeleton function promotes tumor progression [J].
Bourguignon, Lilly Y. W. .
SEMINARS IN CANCER BIOLOGY, 2008, 18 (04) :251-259
[8]   Heregulin-mediated ErbB2-ERK signaling activates hyaluronan synthases leading to CD44-dependent ovarian tumor cell growth and migration [J].
Bourguignon, Lilly Y. W. ;
Gilad, Eli ;
Peyrollier, Karine .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2007, 282 (27) :19426-19441
[9]   Hyaluronan promotes signaling interaction between CD44 and the transforming growth factor β receptor I in metastatic breast tumor cells [J].
Bourguignon, LYW ;
Singleton, PA ;
Zhu, HB ;
Zhou, B .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (42) :39703-39712
[10]   Hyaluronan promotes CD44v3-Vav2 interaction with Grb2-p185HER2 and induces Rac1 and Ras signaling during ovarian tumor cell migration and growth [J].
Bourguignon, LYW ;
Zhu, HB ;
Zhou, B ;
Diedrich, F ;
Singleton, PA ;
Hung, MC .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (52) :48679-48692