Distinct tyrosine autophosphorylation sites mediate induction of epithelial mesenchymal like transition by an activated ErbB-2/Neu receptor

Khoury, Hanane; Dankort, David; Sadekova, Svetlana; Naujokas, Monica A.; Muller, William J.; Park, Morag

doi:10.1038/sj.onc.1204166

Cited by 59 publications

(61 citation statements)

References 33 publications

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“…S3). Our results are consistent with previous findings with HB2 MECs 31 and 32D haematopoietic cells 32 but contrast with those obtained with MDCK 47 and tumour-derived MCF-7 cells 33 . It is likely that ErbB2 is not sufficient to induce invasive behaviour in MCF-10A cells and that additional genetic/epigenetic events or higher levels of ErbB2 expression are required for the cells to acquire invasive behaviour.…”

Section: Discussionsupporting

confidence: 72%

ErbB2, but not ErbB1, reinitiates proliferation and induces luminal repopulation in epithelial acini

et al. 2001

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Both ErbB1 and ErbB2 are overexpressed or amplified in breast tumours. To examine the effects of activating ErbB receptors in a context that mimics polarized epithelial cells in vivo, we activated ErbB1 and ErbB2 homodimers in preformed, growth-arrested mammary acini cultured in threedimensional basement membrane gels. Activation of ErbB2, but not that of ErbB1, led to a reinitiation of cell proliferation and altered the properties of mammary acinar structures. These altered structures share several properties with early-stage tumours, including a loss of proliferative suppression, an absence of lumen, retention of the basement membrane and a lack of invasive properties. ErbB2 activation also disrupted tight junctions and the cell polarity of polarized epithelia, whereas ErbB1 activation did not have any effect. Our results indicate that ErbB receptors differ in their ability to induce early stages of mammary carcinogenesis in vitro and this three-dimensional model system can reveal biological activities of oncogenes that cannot be examined in vitro in standard transformation assays.The mammary epithelium of an adult breast is organized into ducts and lobules. The ducts end in a highly branched structure referred to as the terminal ductal lobular unit (TDLU). A TDLU is comprised of multiple individual units referred to as mammary acini. Each acinus has a central lumen, a single layer of polarized luminal epithelial cells surrounded by myoepithelial cells, and a basement membrane.We have previously shown that human mammary epithelial cells (MECs) form acini-like structures containing a single layer of polarized, growth-arrested cells when grown within a matrix rich in laminin and collagen IV (Matrigel, derived from the Englebreth-Holm Swarm (EHS) tumour) 1,2 . The epithelial cells within acini in vivo and in culture have an apico-basal distribution of polarity markers such as ZO-1, E-cadherin and α 6 β 4 integrins. They also deposit collagen IV and secrete sialomucin in their basal and apical surfaces, respectively 1,2 , indicating that the acinar structures formed in culture closely mimic the acini in an adult breast.Early stages of breast cancer (hyperplasia and ductal carcinoma in situ (DCIS)) are characterized by an increased proliferation of epithelial cells, a loss of acinar organization and § Correspondence and requests for materials should be addressed to J.S.B. joan_brugge@hms.harvard.edu. † Present addresses: Cold Spring Harbor Laboratories, Cold Spring Harbor, New York 11724, USA (S.K.M.); Department of Basic Medical Sciences, Purdue University, West Lafayette, Indiana 47907, USA (S.L.)Supplementary information is available on Nature Cell Biology's website (http://cellbio.nature.com) or as paper copy from the London editorial office of Nature Cell Biology. NIH Public Access Author ManuscriptNat Cell Biol. Author manuscript; available in PMC 2010 October 11. filling of the luminal space 3 . However, a lack of acinar organization and the acquisition of invasive behaviour are later events involved...

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Section: Discussionsupporting

confidence: 72%

ErbB2, but not ErbB1, reinitiates proliferation and induces luminal repopulation in epithelial acini

et al. 2001

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“…Increased expression of Arp2/3 and WAVE2 has been shown to correlate with poor prognosis in breast and liver carcinomas underlining the relevance of lamellipodia-like structures in cancer progression [175,176]. Furthermore, the formation of lamellipodia is also observed upon ErbB2-driven EMT in epithelial cells, indicating that the formation of lamellipodia-like structures underlies the increased invasiveness observed during EMT [177].…”

Section: Lamellipodia and Filopodiamentioning

confidence: 81%

EMT, the cytoskeleton, and cancer cell invasion

Yilmaz

Christofori

2009

Cancer Metastasis Rev

1,534

1,314

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The metastatic process, i.e. the dissemination of cancer cells throughout the body to seed secondary tumors at distant sites, requires cancer cells to leave the primary tumor and to acquire migratory and invasive capabilities. In a process of epithelial-mesenchymal transition (EMT), besides changing their adhesive repertoire, cancer cells employ developmental processes to gain migratory and invasive properties that involve a dramatic reorganization of the actin cytoskeleton and the concomitant formation of membrane protrusions required for invasive growth. The molecular processes underlying such cellular changes are still only poorly understood, and the various migratory organelles, including lamellipodia, filopodia, invadopodia and podosomes, still require a better functional and molecular characterization. Notably, direct experimental evidence linking the formation of migratory membrane protrusions and the process of EMT and tumor metastasis is still lacking. In this review, we have summarized recent novel insights into the molecular processes and players underlying EMT on one side and the formation of invasive membrane protrusions on the other side.

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“…During tumor development in MMTV-c-Neu mice, somatic mutations in the Neu transgene resulting in the formation of an activated form of ErbB2 may promote an epithelial to mesenchymal transition (EMT), and thus downregulate Muc1. Interestingly, work in MDCK cells, a polarized epithelial cell line, showed that the expression of activated ErbB2 favored a fibroblastic phenotype, while wild-type ErbB2 had no effect on cell morphology (Khoury et al, 2001). Moreover, snail, a zinc-finger transcriptional repressor activated during EMT, has been shown to inhibit E-cadherin and MUC1 expression (Guaita et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

Downregulation of Muc1 in MMTV-c-Neu tumors

Adriance

Gendler

2004

Oncogene

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MUC1 is a tumor antigen, overexpressed in approximately 90% of human breast cancers. In normal glandular epithelia, MUC1 is expressed at the apical surface; however, in carcinomas an aberrantly glycosylated form of MUC1 is upregulated and expressed around the entire surface of the cell. Previously, we have shown that a lack of Muc1 significantly delays tumor progression and/or onset in MMTV-PyV-mT and MMTV-Wnt-1 transgenic mice. Here we show that, unlike the models mentioned above, a loss of Muc1 in MMTV-c-Neu mice (MMTV-cNeu/Muc1 À/À ) altered neither mammary tumor onset nor progression. Moreover, characterization of MMTV-cNeu/Muc1 þ / þ tumors revealed that Muc1 expression was repressed at the level of transcription. In contrast, normal mammary gland tissue adjacent to tumor tissue expressed Muc1 and pregnant mammary glands from c-Neu transgenic animals expressed high levels of Muc1. We found that transient transfection of activated ErbB2 into human embryonic kidney 293/MUC1 cells resulted in the repression of MUC1 expression. Further, transient transfection of activated ErbB2 resulted in the inhibition of Muc1 transcriptional activation in luciferase reporter assays. These data suggest that the activation of ErbB2, which only occurs in c-Neu tumors, selectively inhibits Muc1 expression.

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Distinct tyrosine autophosphorylation sites mediate induction of epithelial mesenchymal like transition by an activated ErbB-2/Neu receptor

Cited by 59 publications

References 33 publications

ErbB2, but not ErbB1, reinitiates proliferation and induces luminal repopulation in epithelial acini

ErbB2, but not ErbB1, reinitiates proliferation and induces luminal repopulation in epithelial acini

EMT, the cytoskeleton, and cancer cell invasion

Downregulation of Muc1 in MMTV-c-Neu tumors

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