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  1. Article ; Online: Correction: Halting ErbB-2 isoforms retrograde transport to the nucleus as a new theragnostic approach for triple-negative breast cancer.

    Madera, Santiago / Izzo, Franco / Chervo, María F / Dupont, Agustina / Chiauzzi, Violeta A / Bruni, Sofia / Petrillo, Ezequiel / Merin, Sharon S / De Martino, Mara / Montero, Diego / Levit, Claudio / Lebersztein, Gabriel / Anfuso, Fabiana / Roldán Deamicis, Agustina / Mercogliano, María F / Proietti, Cecilia J / Schillaci, Roxana / Elizalde, Patricia V / Cordo Russo, Rosalía I

    Cell death & disease

    2023  Volume 14, Issue 12, Page(s) 833

    Language English
    Publishing date 2023-12-15
    Publishing country England
    Document type Published Erratum
    ZDB-ID 2541626-1
    ISSN 2041-4889 ; 2041-4889
    ISSN (online) 2041-4889
    ISSN 2041-4889
    DOI 10.1038/s41419-023-06339-1
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Blocking soluble TNFα sensitizes HER2-positive breast cancer to trastuzumab through MUC4 downregulation and subverts immunosuppression.

    Bruni, Sofia / Mauro, Florencia L / Proietti, Cecilia J / Cordo-Russo, Rosalia I / Rivas, Martin A / Inurrigarro, Gloria / Dupont, Agustina / Rocha, Dario / Fernández, Elmer A / Deza, Ernesto Gil / Lopez Della Vecchia, Daniel / Barchuk, Sabrina / Figurelli, Silvina / Lasso, David / Friedrich, Adrián D / Santilli, María C / Regge, María V / Lebersztein, Gabriel / Levit, Claudio /
    Anfuso, Fabiana / Castiglione, Teresa / Elizalde, Patricia V / Mercogliano, Maria F / Schillaci, Roxana

    Journal for immunotherapy of cancer

    2023  Volume 11, Issue 3

    Abstract: Background: The success of HER2-positive (HER2+) breast cancer treatment with trastuzumab, an antibody that targets HER2, relies on immune response. We demonstrated that TNFα induces mucin 4 (MUC4) expression, which shields the trastuzumab epitope on ... ...

    Abstract Background: The success of HER2-positive (HER2+) breast cancer treatment with trastuzumab, an antibody that targets HER2, relies on immune response. We demonstrated that TNFα induces mucin 4 (MUC4) expression, which shields the trastuzumab epitope on the HER2 molecule decreasing its therapeutic effect. Here, we used mouse models and samples from HER2+ breast cancer patients to unravel MUC4 participation in hindering trastuzumab effect by fostering immune evasion.
    Methods: We used a dominant negative TNFα inhibitor (DN) selective for soluble TNFα (sTNFα) together with trastuzumab. Preclinical experiments were performed using two models of conditionally MUC4-silenced tumors to characterize the immune cell infiltration. A cohort of 91 patients treated with trastuzumab was used to correlate tumor MUC4 with tumor-infiltrating lymphocytes.
    Results: In mice bearing de novo trastuzumab-resistant HER2+ breast tumors, neutralizing sTNFα with DN induced MUC4 downregulation. Using the conditionally MUC4-silenced tumor models, the antitumor effect of trastuzumab was reinstated and the addition of TNFα-blocking agents did not further decrease tumor burden. DN administration with trastuzumab modifies the immunosuppressive tumor milieu through M1-like phenotype macrophage polarization and NK cells degranulation. Depletion experiments revealed a cross-talk between macrophages and NK cells necessary for trastuzumab antitumor effect. In addition, tumor cells treated with DN are more susceptible to trastuzumab-dependent cellular phagocytosis. Finally, MUC4 expression in HER2+ breast cancer is associated with immune desert tumors.
    Conclusions: These findings provide rationale to pursue sTNFα blockade combined with trastuzumab or trastuzumab drug conjugates for MUC4+ and HER2+ breast cancer patients to overcome trastuzumab resistance.
    MeSH term(s) Mice ; Animals ; Trastuzumab/pharmacology ; Trastuzumab/therapeutic use ; Down-Regulation ; Mucin-4/genetics ; Mucin-4/metabolism ; Tumor Necrosis Factor-alpha/metabolism ; Receptor, ErbB-2 ; Cell Line, Tumor ; Immunosuppression Therapy ; Neoplasms/drug therapy
    Chemical Substances Trastuzumab (P188ANX8CK) ; Mucin-4 ; Tumor Necrosis Factor-alpha ; Receptor, ErbB-2 (EC 2.7.10.1)
    Language English
    Publishing date 2023-03-08
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2719863-7
    ISSN 2051-1426 ; 2051-1426
    ISSN (online) 2051-1426
    ISSN 2051-1426
    DOI 10.1136/jitc-2022-005325
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Halting ErbB-2 isoforms retrograde transport to the nucleus as a new theragnostic approach for triple-negative breast cancer.

    Madera, Santiago / Izzo, Franco / Chervo, María F / Dupont, Agustina / Chiauzzi, Violeta A / Bruni, Sofia / Petrillo, Ezequiel / Merin, Sharon S / De Martino, Mara / Montero, Diego / Levit, Claudio / Lebersztein, Gabriel / Anfuso, Fabiana / Roldán Deamicis, Agustina / Mercogliano, María F / Proietti, Cecilia J / Schillaci, Roxana / Elizalde, Patricia V / Cordo Russo, Rosalía I

    Cell death & disease

    2022  Volume 13, Issue 5, Page(s) 447

    Abstract: Triple-negative breast cancer (TNBC) is clinically defined by the absence of estrogen and progesterone receptors and the lack of membrane overexpression or gene amplification of receptor tyrosine kinase ErbB-2/HER2. Due to TNBC heterogeneity, clinical ... ...

    Abstract Triple-negative breast cancer (TNBC) is clinically defined by the absence of estrogen and progesterone receptors and the lack of membrane overexpression or gene amplification of receptor tyrosine kinase ErbB-2/HER2. Due to TNBC heterogeneity, clinical biomarkers and targeted therapies for this disease remain elusive. We demonstrated that ErbB-2 is localized in the nucleus (NErbB-2) of TNBC cells and primary tumors, from where it drives growth. We also discovered that TNBC expresses both wild-type ErbB-2 (WTErbB-2) and alternative ErbB-2 isoform c (ErbB-2c). Here, we revealed that the inhibitors of the retrograde transport Retro-2 and its cyclic derivative Retro-2.1 evict both WTErbB-2 and ErbB-2c from the nucleus of BC cells and tumors. Using BC cells from several molecular subtypes, as well as normal breast cells, we demonstrated that Retro-2 specifically blocks proliferation of BC cells expressing NErbB-2. Importantly, Retro-2 eviction of both ErbB-2 isoforms from the nucleus resulted in a striking growth abrogation in multiple TNBC preclinical models, including tumor explants and xenografts. Our mechanistic studies in TNBC cells revealed that Retro-2 induces a differential accumulation of WTErbB-2 at the early endosomes and the plasma membrane, and of ErbB-2c at the Golgi, shedding new light both on Retro-2 action on endogenous protein cargoes undergoing retrograde transport, and on the biology of ErbB-2 splicing variants. In addition, we revealed that the presence of a functional signal peptide and a nuclear export signal (NES), both located at the N-terminus of WTErbB-2, and absent in ErbB-2c, accounts for the differential subcellular distribution of ErbB-2 isoforms upon Retro-2 treatment. Our present discoveries provide evidence for the rational repurposing of Retro-2 as a novel therapeutic agent for TNBC.
    MeSH term(s) Cell Nucleus/metabolism ; Humans ; Protein Isoforms/genetics ; Protein Isoforms/metabolism ; Receptor, ErbB-2/metabolism ; Receptors, Progesterone/metabolism ; Triple Negative Breast Neoplasms/pathology
    Chemical Substances Protein Isoforms ; Receptors, Progesterone ; Receptor, ErbB-2 (EC 2.7.10.1)
    Language English
    Publishing date 2022-05-09
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2541626-1
    ISSN 2041-4889 ; 2041-4889
    ISSN (online) 2041-4889
    ISSN 2041-4889
    DOI 10.1038/s41419-022-04855-0
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Nuclear PDCD4 Expression Defines a Subset of Luminal B-Like Breast Cancers with Good Prognosis.

    Madera, Santiago / Chervo, María F / Chiauzzi, Violeta A / Pereyra, Matías G / Venturutti, Leandro / Izzo, Franco / Roldán Deamicis, Agustina / Guzman, Pablo / Dupont, Agustina / Roa, Juan Carlos / Cenciarini, Mauro E / Barchuk, Sabrina / Figurelli, Silvina / Lopez Della Vecchia, Daniel / Levit, Claudio / Lebersztein, Gabriel / Anfuso, Fabiana / Castiglioni, Teresa / Cortese, Eduardo /
    Ares, Sandra / Deza, Ernesto Gil / Gercovich, Felipe G / Proietti, Cecilia J / Schillaci, Roxana / Cordo Russo, Rosalía I / Elizalde, Patricia V

    Hormones & cancer

    2020  Volume 11, Issue 5-6, Page(s) 218–239

    Abstract: The hormone receptor-positive (estrogen and/or progesterone receptor (PR)-positive) and HER2-negative breast cancer (BC) subtype is a biologically heterogeneous entity that includes luminal A-like (LumA-like) and luminal B-like (LumB-like) subtypes. ... ...

    Abstract The hormone receptor-positive (estrogen and/or progesterone receptor (PR)-positive) and HER2-negative breast cancer (BC) subtype is a biologically heterogeneous entity that includes luminal A-like (LumA-like) and luminal B-like (LumB-like) subtypes. Decreased PR levels is a distinctive biological feature of LumB-like tumors. These tumors also show reduced sensitivity to endocrine therapies and poorer prognosis than LumA-like tumors. Identification of biomarkers to accurately predict disease relapse in these subtypes is crucial in order to select effective therapies. We identified the tumor suppressor PDCD4 (programmed cell death 4), located in the nucleus (NPDCD4), as an independent prognostic factor of good clinical outcome in LumA-like and LumB-like subtypes. NPDCD4-positive LumB-like tumors presented overall and disease-free survival rates comparable to those of NPDCD4-positive LumA-like tumors, indicating that NPDCD4 improves the outcome of LumB-like patients. In contrast, NPDCD4 loss increased the risk of disease recurrence and death in LumB-like compared with LumA-like tumors. This, along with our results showing that LumB-like tumors present lower NPDCD4 positivity than LumA-like tumors, suggests that NPDCD4 loss contributes to endocrine therapy resistance in LumB-like BCs. We also revealed that PR induces PDCD4 transcription in LumB-like BC, providing a mechanistic explanation to the low PDCD4 levels in LumB-like BCs lacking PR. Finally, PDCD4 silencing enhanced BC cell survival in a patient-derived explant model of LumB-like disease. Our discoveries highlight NPDCD4 as a novel biomarker in LumA- and LumB-like subtypes, which could be included in the panel of immunohistochemical markers used in the clinic to accurately predict the prognosis of LumB-like tumors.
    MeSH term(s) Apoptosis Regulatory Proteins/metabolism ; Breast Neoplasms/genetics ; Breast Neoplasms/pathology ; Female ; Humans ; Prognosis ; RNA-Binding Proteins/metabolism
    Chemical Substances Apoptosis Regulatory Proteins ; PDCD4 protein, human ; RNA-Binding Proteins
    Language English
    Publishing date 2020-07-06
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2543318-0
    ISSN 1868-8500 ; 1868-8500
    ISSN (online) 1868-8500
    ISSN 1868-8500
    DOI 10.1007/s12672-020-00392-4
    Database MEDical Literature Analysis and Retrieval System OnLINE

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