Correlated break at PARK2/FRA6E and loss of AF-6/Afadin protein expression are associated with poor outcome in breast cancer

Letessier, A; Garrido‐Urbani, Sarah; Ginestier, Christophe; Fournier, Gilles; Esterni, Benjamin; Monville, Florence; Adélaı̈de, José; Geneix, Jeannine; Xerri, Luc; Dubreuil, Patrice; Viens, Patrice; Charafe-Jauffret, Emmanuelle; Jacquemier, Jocelyne; Birnbaum, Daniel; Lopez, Marc; Chaffanet, Max

doi:10.1038/sj.onc.1209772

Cited by 85 publications

(77 citation statements)

References 52 publications

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“…Nectin-4 is an antigen mainly expressed during embryogenesis and highly expressed (68%) in tumors of breast origin [20,21]. Nectin-4 staining has been described as prevalent cytoplasmic and discrete membrane stain [54][55][56].…”

Section: Discussionmentioning

confidence: 99%

The significance of Survivin and Nectin-4 expression in the prognosis of breast carcinoma

Athanassiadou¹,

Patsouris²,

Tsipis³

et al. 2011

Folia Histochem Cytobiol.

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Abstract:To investigate the prognostic significance of Survivin and Nectin-4 expression in breast carcinomas. Imprint smears were obtained from 140 breast carcinoma specimens and studied immunocytochemically for the expression of Survivin and Nectin-4. The results were correlated with several clinicopathological parameters, including five-year survival. Increased Survivin staining pattern correlated with increased grade (p < 0.0001), increased lymph node invasion (p < 0.0001), increased tumor size and reduced survival (p < 0.0001). Elevated Nectin-4 expression also correlated significantly with increased grade (p < 0.0001), increased tumor size (p < 0.0001) and reduced survival (p < 0.0001). In addition, Survivin and Nectin-4 staining patterns correlated strongly with one another (p < 0.0001). However, on multivariate analysis, neither Survivin nor Nectin-4 expression seemed to have an independent impact on survival in our study cases. The findings of our study suggest that increased expression of Survivin and Nectin-4 may indicate a worse prognosis in breast cancer patients. The exact implications of the expression of these markers in breast cancer prognosis and treatment remain to be

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Section: Discussionmentioning

confidence: 99%

The significance of Survivin and Nectin-4 expression in the prognosis of breast carcinoma

Athanassiadou¹,

Patsouris²,

Tsipis³

et al. 2011

Folia Histochem Cytobiol.

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“…The phenotypic changes observed with these mice include disorganization of the ectoderm, impaired migration of the mesoderm and loss of somites or other structures derived from both the ectoderm and the mesoderm 10,11 . Recently, expression of the AF6 gene was found to be aberrant in multiple cancer types, including leukaemia, ovarian and breast cancers 3,4,[12][13][14][15][16] , but the specific roles that AF6 might play in tumorigenesis remain unclear.…”

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confidence: 99%

Loss of polarity protein AF6 promotes pancreatic cancer metastasis by inducing Snail expression

Chang

Peng

et al. 2015

Nat Commun

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Pancreatic cancer (PC) is a particularly lethal form of cancer with high potential for metastasis to distant organs. Disruption of cell polarity is a hallmark of advanced epithelial tumours. Here we show that the polarity protein AF6 (afadin and MLLT4) is expressed at low levels in PC. We demonstrate that depletion of AF6 markedly promotes proliferation and metastasis of PC cells through upregulation of the expression of Snail protein, and this requires the nuclear localization of AF6. Furthermore, AF6 deficiency in PC cells leads to increased formation of a Dishevelled 2 (Dvl2)-FOXE1 complex on the promoter region of Snail gene, and activation of Snail expression. Altogether, our data established AF6 as a potential inhibitor of metastasis in PC cells. Targeting the Dvl2-FOXE1-Snail signalling axis may thus represent a promising therapeutic strategy.

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“…Parkin gene mutations have been implicated in the pathogenesis of Parkinson's disease and cancer [7][8][9][10][11]. In addition, break at the Parkin gene/common fragile site FRA6E is associated with poor outcome in breast cancer [27]. In this study, our results provide evidence to support a novel function for Parkin in regulating the sensitivity of breast cancer cells to paclitaxel: (a) Parkin increases the ability of paclitaxel to trigger multinucleation and apoptosis; (b) Parkin renders breast cancer cell lines more sensitive to paclitaxel; and (c) Parkin expression correlates with the sensitivity of paclitaxel in primary cultures of breast cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Parkin regulates paclitaxel sensitivity in breast cancer via a microtubule‐dependent mechanism

Wang

Liu

Zhang

et al. 2009

The Journal of Pathology

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Parkin is an E3 ubiquitin ligase encoded by the Parkin gene (also called PARK2, located at 6q25.2-q27) and is involved in the pathogenesis of Parkinson's disease and the development of cancer. Recently, Parkin has been demonstrated to interact with the microtubule cytoskeleton. However, the biological implication of the Parkin-microtubule axis has been poorly explored. In this study, we report for the first time that Parkin modulates sensitivity of the chemotherapeutic agent paclitaxel in breast cancer, via a microtubule-dependent mechanism. Our data reveal that Parkin binds to the outer surface of microtubules and increases paclitaxel-microtubule interaction, resulting in enhanced paclitaxel-induced microtubule assembly and stabilization. Our data further show that Parkin promotes the activity of paclitaxel to trigger multinucleation and apoptosis, rendering breast cancer cells more sensitive to this drug. Moreover, Parkin expression correlates with the pathological response of tumours to preoperative paclitaxel-containing chemotherapy. In addition, expression of Parkin also correlates with the sensitivity of paclitaxel in primary cultures of breast cancer cells. Our results identify Parkin as a novel mediator of paclitaxel sensitivity in breast cancer. In addition, our study suggests that patients harbouring tumours with high Parkin level would be more likely to benefit from paclitaxel-containing regimens.

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Correlated break at PARK2/FRA6E and loss of AF-6/Afadin protein expression are associated with poor outcome in breast cancer

Cited by 85 publications

References 52 publications

The significance of Survivin and Nectin-4 expression in the prognosis of breast carcinoma

The significance of Survivin and Nectin-4 expression in the prognosis of breast carcinoma

Loss of polarity protein AF6 promotes pancreatic cancer metastasis by inducing Snail expression

Parkin regulates paclitaxel sensitivity in breast cancer via a microtubule‐dependent mechanism

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