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. MamBo89HER2stable cell line displayed high and stable HER2 expression, which was maintained upon in vivo passages, whereas MamBo43HER2labile cell line gave rise to HER2-negative tumors from which MamBo38HER2loss cell line was derived. Both low-density seeding and in vitro trastuzumab treatment of MamBo43HER2labile cells induced the loss of HER2 expression. MamBo38HER2loss 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 MamBo38HER2loss cell tumorigenic ability. Sunitinib inhibited MamBo38HER2loss 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.
Highlights
Breast cancer is a major clinical problem and is the most frequent cause of death by tumor in women [1]
We have reported a spontaneous model of HER2 loss in which the loss of HER2 expression is associated with a spindle-like morphology, increased IL-6 production, a gene expression profile that is reminiscent of Epithelial-to-mesenchymal transition (EMT), increased stemness features and malignancy in vivo
We have proposed a dynamic model of HER2-positive mammary tumors that tends to spontaneously lose HER2 expression and progress towards a more aggressive phenotype via the acquisition of EMT and stemness properties, which are distinctive traits of claudin-low tumors
Summary
Breast cancer is a major clinical problem and is the most frequent cause of death by tumor in women [1]. Breast cancer is not a single entity, but rather a multitude of diseases that include several subtypes with extremely different molecular, morphological and clinical characteristics [2]. A certain degree of molecular and clinical heterogeneity was found even within each intrinsic subtype [3]. HER2-enriched tumors account for 20–25% of breast cancers, and anti-HER2 targeted drugs significantly improved the survival rate of these patients [4]. HER2-positive breast cancer still presents a challenge for clinicians and researchers, mainly due to high rates of intrinsic and acquired resistance to HER2-targeted therapies, and brain metastasis [5]
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