Clinical relevance of ErbB-2/HER2 nuclear expression in breast cancer

Schillaci, Roxana; Guzmán, Pablo; Cayrol, Florencia; Béguelin, Wendy; Flaqué, María Celeste Díaz; Proietti, Cecilia J.; Pineda, Viviana; Palazzi, Jorge; Frahm, Isabel; Maronna, Esteban; Roa, Juan Carlos; Elizalde, Patricia V.

doi:10.1186/1471-2407-12-74

Cited by 44 publications

(31 citation statements)

References 37 publications

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“…MErbB-2, NErbB-2, and NStat3 were studied and scored as we reported. 13,50 The expression of PDCD4, mostly a nuclear protein in BC, 51,52 was studied by immunohistochemistry and scored on a 0 to 3 scale as described in Materials and Methods. Scores of 2+ and 3+ were considered positive (Supplementary Figure S6a).…”

Section: Mir-21 Induced By the Stat3/erbb-2 Transcriptional Complex Dmentioning

confidence: 99%

Stat3 regulates ErbB-2 expression and co-opts ErbB-2 nuclear function to induce miR-21 expression, PDCD4 downregulation and breast cancer metastasis

et al. 2015

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Membrane overexpression of the receptor tyrosine kinase ErbB-2 (MErbB-2) accounts for a clinically aggressive breast cancer (BC) subtype (ErbB-2-positive) with increased incidence of metastases. We and others demonstrated that nuclear ErbB-2 (NErbB-2) also plays a key role in BC and is a poor prognostic factor in ErbB-2-positive tumors. The signal transducer and activator of transcription 3 (Stat3), another player in BC, has been recognized as a downstream mediator of MErbB-2 action in BC metastasis. Here, we revealed an unanticipated novel direction of the ErbB-2 and Stat3 interaction underlying BC metastasis. We found that Stat3 binds to its response elements (GAS) at the ErbB-2 promoter to upregulate ErbB-2 transcription in metastatic, ErbB-2-positive BC. We validated these results in several BC subtypes displaying metastatic and non-metastatic ability, highlighting Stat3 general role as upstream regulator of ErbB-2 expression in BC. Moreover, we showed that Stat3 co-opts NErbB-2 function by recruiting ErbB-2 as its coactivator at the GAS sites in the promoter of microRNA-21 (miR-21), a metastasis-promoting microRNA (miRNA). Using an ErbB-2 nuclear localization domain mutant and a constitutively activated ErbB-2 variant, we found that NErbB-2 role as a Stat3 coactivator and also its direct role as transcription factor upregulate miR-21 in BC. This reveals a novel function of NErbB-2 as a regulator of miRNAs expression. Increased levels of miR-21, in turn, downregulate the expression of the metastasis-suppressor protein programmed cell death 4 (PDCD4), a validated miR-21 target. Using an in vivo model of metastatic ErbB-2-postive BC, in which we silenced Stat3 and reconstituted ErbB-2 or miR-21 expression, we showed that both are downstream mediators of Stat3-driven metastasis. Supporting the clinical relevance of our results, we found an inverse correlation between ErbB-2/Stat3 nuclear co-expression and PDCD4 expression in ErbB-2-positive primary invasive BCs. Our findings identify Stat3 and NErbB-2 as novel therapeutic targets to inhibit ErbB-2-positive BC metastasis.

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Section: Mir-21 Induced By the Stat3/erbb-2 Transcriptional Complex Dmentioning

confidence: 99%

Stat3 regulates ErbB-2 expression and co-opts ErbB-2 nuclear function to induce miR-21 expression, PDCD4 downregulation and breast cancer metastasis

et al. 2015

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“…Pretreatment patient staging was classified according to the system of the American Joint Committee on Cancer (AJCC; Singletary et al 2002) through the Elston and Ellis histological grading (Page et al 1995). TMAs were constructed as described earlier (Schillaci et al 2012).…”

Section: Patients and Tissue Microarraysmentioning

confidence: 99%

“…Immunofluorescence was performed as described previously (Schillaci et al 2012), using the mouse monoclonal anti-pStat3Ser727 (6E4) antibody (dilution 1:50 overnight at 4 8C; Cell Signaling). Slides were then incubated with an anti-mouse Alexa 488-conjugated antibody (1:1000, Molecular Probes).…”

Section: Immunofluorescence and Immunohistochemistry Analysis Of Tmasmentioning

confidence: 99%

“…A score of one or more was required for tumor sample to be considered positive for nuclear pStat3Ser727 expression (Sato et al 2011). ER and PR were evaluated by immunohistochemistry (IHC) with clone 6F11 (Novocastra Laboratories, UK) and clone hPRa2ChPRa3 (NeoMarkers) respectively and scored as described (Schillaci et al 2012).…”

Section: Immunofluorescence and Immunohistochemistry Analysis Of Tmasmentioning

confidence: 99%

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p42/p44 MAPK-mediated Stat3Ser727 phosphorylation is required for progestin-induced full activation of Stat3 and breast cancer growth

Tkach¹,

Rosemblit²,

Rivas³

et al. 2013

Endocrine-Related Cancer

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Stat3 is a signaling node for multiple oncogenic pathways and is therefore frequently active in breast cancer. As experimental and clinical evidence reveals that progestins are key players in controlling mammary gland tumorigenesis, we studied Stat3 participation in this event.We have previously shown that progestins induce Stat3Tyr705 phosphorylation and its transcriptional activation in breast cancer cells. In this study, we demonstrate that progestins also induce Stat3 phosphorylation at Ser727 residue, which occurs via activation of c-Src/p42/p44 MAPK pathways in murine progestin-dependent C4HD cells and in T-47D cells. Expression of a Stat3S727A vector, which carries a serine-to-alanine substitution at codon 727, shows that Stat3Ser727 phosphorylation is required for full transcriptional activation of cyclin D1 gene expression by progestins and for in vivo Stat3 recruitment on cyclin D1 promoter. Transfection of Stat3S727A in murine and human breast cancer cells abolished progestin-induced in vitro and in vivo growth. Moreover, we found a positive correlation between progesterone receptor expression and nuclear localization of Stat3Ser727 phosphorylation in breast cancer biopsies. These data highlight Stat3 phosphorylation in Ser727 residue as a nongenomic action by progestins, necessary to promote breast cancer growth.

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“…In this study, both nuclear ErbB-2 and COX-2 were associated with reduced disease-free survival in patients receiving tamoxifen in the adjuvant setting (Dillon et al 2008). More recent clinical studies in a small cohort of primary invasive BCs revealed a role for nuclear ErbB-2 as an independent prognostic factor of poor clinical outcome in MErbB-2-positive tumors (Schillaci et al 2012). …”

Section: Clinical Significance Of Nuclear Erbb-2 As a Biomarker In Bcmentioning

confidence: 92%

ErbB-2 nuclear function in breast cancer growth, metastasis and resistance to therapy

Elizalde¹,

Russo²,

Chervo³

et al. 2016

Endocrine-Related Cancer

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Approximately 15-20% of breast cancers (BC) show either membrane overexpression of ErbB-2 (MErbB-2), a member of the ErbBs family of receptor tyrosine kinases, or ERBB2 gene amplification. Until the development of MErbB-2-targeted therapies, this BC subtype, called ErbB-2-positive, was associated with increased metastatic potential and poor prognosis. Although these therapies have significantly improved overall survival and cure rates, resistance to available drugs is still a major clinical issue. In its classical mechanism, MErbB-2 activates downstream signaling cascades, which transduce its effects in BC. The fact that ErbB-2 is also present in the nucleus of BC cells was discovered over twenty years ago. Also, compelling evidence revealed a non-canonical function of nuclear ErbB-2 as a transcriptional regulator. As a deeper understanding of nuclear ErbB-2 actions would be crucial to the disclosure of its role as a biomarker and a target of therapy in BC, we will here review its function in BC, in particular, its role in growth, metastatic spreading and response to currently available MErbB-2-positive BC therapies.

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Clinical relevance of ErbB-2/HER2 nuclear expression in breast cancer

Cited by 44 publications

References 37 publications

Stat3 regulates ErbB-2 expression and co-opts ErbB-2 nuclear function to induce miR-21 expression, PDCD4 downregulation and breast cancer metastasis

Stat3 regulates ErbB-2 expression and co-opts ErbB-2 nuclear function to induce miR-21 expression, PDCD4 downregulation and breast cancer metastasis

p42/p44 MAPK-mediated Stat3Ser727 phosphorylation is required for progestin-induced full activation of Stat3 and breast cancer growth

ErbB-2 nuclear function in breast cancer growth, metastasis and resistance to therapy

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