Evolution of HER2-positive mammary carcinoma: HER2 loss reveals claudin-low traits in cancer progression

Abstract HER2-positive breast cancers may lose HER2 expression in recurrences and metastases. In this work, we studied cell lines derived from two transgenic mammary tumors driven by human HER2 that showed different dynamics of HER2 status. MamBo89HER2 stable cell line displayed high and stable HER2...

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Autores principales:	Veronica Giusti, Francesca Ruzzi, Lorena Landuzzi, Marianna L. Ianzano, Roberta Laranga, Elena Nironi, Laura Scalambra, Giordano Nicoletti, Carla De Giovanni, Martina Olivero, Maddalena Arigoni, Raffaele Calogero, Patrizia Nanni, Arianna Palladini, Pier-Luigi Lollini
Formato:	article
Lenguaje:	EN
Publicado:	Nature Publishing Group 2021
Materias:	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/b560bd2ffc044642b16dd92b9b06a0fa
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spelling	oai:doaj.org-article:b560bd2ffc044642b16dd92b9b06a0fa2021-11-14T12:16:46ZEvolution of HER2-positive mammary carcinoma: HER2 loss reveals claudin-low traits in cancer progression10.1038/s41389-021-00360-92157-9024https://doaj.org/article/b560bd2ffc044642b16dd92b9b06a0fa2021-11-01T00:00:00Zhttps://doi.org/10.1038/s41389-021-00360-9https://doaj.org/toc/2157-9024Abstract HER2-positive breast cancers may lose HER2 expression in recurrences and metastases. In this work, we studied cell lines derived from two transgenic mammary tumors driven by human HER2 that showed different dynamics of HER2 status. MamBo89HER2 stable cell line displayed high and stable HER2 expression, which was maintained upon in vivo passages, whereas MamBo43HER2 labile cell line gave rise to HER2-negative tumors from which MamBo38HER2 loss cell line was derived. Both low-density seeding and in vitro trastuzumab treatment of MamBo43HER2 labile cells induced the loss of HER2 expression. MamBo38HER2 loss cells showed a spindle-like morphology, high stemness and acquired in vivo malignancy. A comprehensive molecular profile confirmed the loss of addiction to HER2 signaling and acquisition of an EMT signature, together with increased angiogenesis and migration ability. We identified PDGFR-B among the newly expressed determinants of MamBo38HER2 loss cell tumorigenic ability. Sunitinib inhibited MamBo38HER2 loss tumor growth in vivo and reduced stemness and IL6 production in vitro. In conclusion, HER2-positive mammary tumors can evolve into tumors that display distinctive traits of claudin-low tumors. Our dynamic model of HER2 status can lead to the identification of new druggable targets, such as PDGFR-B, in order to counteract the resistance to HER2-targeted therapy that is caused by HER2 loss.Veronica GiustiFrancesca RuzziLorena LanduzziMarianna L. IanzanoRoberta LarangaElena NironiLaura ScalambraGiordano NicolettiCarla De GiovanniMartina OliveroMaddalena ArigoniRaffaele CalogeroPatrizia NanniArianna PalladiniPier-Luigi LolliniNature Publishing GrouparticleNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENOncogenesis, Vol 10, Iss 11, Pp 1-12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Veronica Giusti Francesca Ruzzi Lorena Landuzzi Marianna L. Ianzano Roberta Laranga Elena Nironi Laura Scalambra Giordano Nicoletti Carla De Giovanni Martina Olivero Maddalena Arigoni Raffaele Calogero Patrizia Nanni Arianna Palladini Pier-Luigi Lollini Evolution of HER2-positive mammary carcinoma: HER2 loss reveals claudin-low traits in cancer progression
description	Abstract HER2-positive breast cancers may lose HER2 expression in recurrences and metastases. In this work, we studied cell lines derived from two transgenic mammary tumors driven by human HER2 that showed different dynamics of HER2 status. MamBo89HER2 stable cell line displayed high and stable HER2 expression, which was maintained upon in vivo passages, whereas MamBo43HER2 labile cell line gave rise to HER2-negative tumors from which MamBo38HER2 loss cell line was derived. Both low-density seeding and in vitro trastuzumab treatment of MamBo43HER2 labile cells induced the loss of HER2 expression. MamBo38HER2 loss cells showed a spindle-like morphology, high stemness and acquired in vivo malignancy. A comprehensive molecular profile confirmed the loss of addiction to HER2 signaling and acquisition of an EMT signature, together with increased angiogenesis and migration ability. We identified PDGFR-B among the newly expressed determinants of MamBo38HER2 loss cell tumorigenic ability. Sunitinib inhibited MamBo38HER2 loss tumor growth in vivo and reduced stemness and IL6 production in vitro. In conclusion, HER2-positive mammary tumors can evolve into tumors that display distinctive traits of claudin-low tumors. Our dynamic model of HER2 status can lead to the identification of new druggable targets, such as PDGFR-B, in order to counteract the resistance to HER2-targeted therapy that is caused by HER2 loss.
format	article
author	Veronica Giusti Francesca Ruzzi Lorena Landuzzi Marianna L. Ianzano Roberta Laranga Elena Nironi Laura Scalambra Giordano Nicoletti Carla De Giovanni Martina Olivero Maddalena Arigoni Raffaele Calogero Patrizia Nanni Arianna Palladini Pier-Luigi Lollini
author_facet	Veronica Giusti Francesca Ruzzi Lorena Landuzzi Marianna L. Ianzano Roberta Laranga Elena Nironi Laura Scalambra Giordano Nicoletti Carla De Giovanni Martina Olivero Maddalena Arigoni Raffaele Calogero Patrizia Nanni Arianna Palladini Pier-Luigi Lollini
author_sort	Veronica Giusti
title	Evolution of HER2-positive mammary carcinoma: HER2 loss reveals claudin-low traits in cancer progression
title_short	Evolution of HER2-positive mammary carcinoma: HER2 loss reveals claudin-low traits in cancer progression
title_full	Evolution of HER2-positive mammary carcinoma: HER2 loss reveals claudin-low traits in cancer progression
title_fullStr	Evolution of HER2-positive mammary carcinoma: HER2 loss reveals claudin-low traits in cancer progression
title_full_unstemmed	Evolution of HER2-positive mammary carcinoma: HER2 loss reveals claudin-low traits in cancer progression
title_sort	evolution of her2-positive mammary carcinoma: her2 loss reveals claudin-low traits in cancer progression
publisher	Nature Publishing Group
publishDate	2021
url	https://doaj.org/article/b560bd2ffc044642b16dd92b9b06a0fa
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Evolution of HER2-positive mammary carcinoma: HER2 loss reveals claudin-low traits in cancer progression

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