Flotillins as regulators of ErbB2 levels in breast cancer

Abstract

Amplification and overexpression of the receptor tyrosine kinase ErbB2 occur in up to 30% of human breast cancers, and high ErbB2 levels are correlated with poor prognosis for breast cancer patients. In contrast to the epithelial growth factor receptor (ErbB1), ErbB2 is not downregulated by ligand-induced mechanisms. Here we show that flotillins are involved in the stabilization of ErbB2 at the plasma membrane. In SKBR3 breast cancer cells and breast cancer tissue, a positive correlation between flotillin and ErbB2 expression levels could be demonstrated. Moreover, the tissue microarray analyses of biopsies from 194 patients diagnosed with carcinomas of the breast showed that flotillin-2 emerged as a potential predictor of prognosis in breast cancer. Depletion of flotillin-1 and flotillin-2 leads to internalization and degradation of ErbB2. Furthermore, flotillin-1 and -2 were found to be in a molecular complex with ErbB2 and Hsp90. The depletion of one of these proteins results in disruption of this complex, followed by destabilization of ErbB2 at the membrane, and its internalization and degradation. As a consequence, ErbB2-triggered downstream signalling is inhibited. Our data demonstrate a novel mechanism for interfering with ErbB2 signalling, which potentially can have clinical impact.

Flotillins in intercellular adhesion – from cellular physiology to human diseases

“…Although flotillins clearly mediate the clustering or the stabilization of various proteins, such as APP (Schneider et al, 2008), EGF receptor (EGFR) (Amaddii et al, 2012) and the ligand-less EGFR family member ErbB2 (Pust et al, 2013) at the plasma membrane, under some circumstances, they could also induce their endocytosis. It will therefore be important to elucidate the molecular pathways that govern the functions of flotillin in either stabilization or endocytosis of plasma membrane proteins.…”

“…In particular, it will be interesting to determine whether flotillin overexpression influences the cross-talk between cadherins and EGFRs, because activation of signaling pathways downstream of EGFRs, particularly of Rho GTPases, which are key regulators of tumor cell migration and invasion (Vega and Ridley, 2008), induces cadherin destabilization (Fukata and Kaibuchi, 2001;Lanzetti et al, 2000). Interestingly, in breast and gastric tumors, flotillin 2 expression positively correlates with the expression of the EGFR ErbB2 Zhu et al, 2013), and, in these cells, flotillin 2 has been shown to stabilize this receptor at the plasma membrane (Pust et al, 2013). Moreover, flotillin 1 is required for the activation of EGFRdependent signaling, both with regard to EGFR phosphorylation and subsequent MAPK activation (Amaddii et al, 2012).…”

“…Moreover, the genomic region containing the flotillin 2 gene is amplified in breast cancer tumors (Berger et al, 2013). Flotillin upregulation is detected in several types of cancers and it is associated with poor patient survival prognosis and high risk of metastasis formation (Doherty et al, 2006;Hazarika et al, 2004;Li et al, 2013;Pust et al, 2013;Rickman et al, 2008;Wang et al, 2013;Zhang et al, 2013;Zhu et al, 2013). In vivo analysis of the role of flotillins during tumorigenesis using a transgenic mouse model of breast cancer has shown that flotillin 2 is not involved in primary tumor formation, but is an important regulator of mammary-tumorderived lung metastasis (Berger et al, 2013).…”

“…Possible role of flotillins in Src-family-kinase-dependent regulation of cadherin complexes Phosphorylation is also important for the regulation of adherens junction dynamics, although the exact events are still not very well known (Bertocchi et al, 2012;Pust et al, 2013). Src family kinases, which are recruited to cell-cell junctions upon cadherin binding, are regulators of cadherin-mediated adhesion and also affect flotillin function (Babuke et al, 2009;Bertocchi et al, 2012;NeumannGiesen et al, 2007;Riento et al, 2009).…”

Essential role of flotillin-1 palmitoylation in the intracellular localization and signaling function of IGF-1 receptor

“…Flotillin-1 palmitoylation is known to be required for its plasma membrane targeting (Liu et al, 2005;Morrow et al, 2002) and for protein kinase C (PKC)-induced endocytosis of dopamine transporter (Cremona et al, 2011). Recently, it has been shown that flotillin-1 and/or flotillin-2 can mediate receptor endocytosis, recycling and lysosomal targeting (Cremona et al, 2011;Pust et al, 2013;Solis et al, 2013). However, the regulatory role of flotillin palmitoylation in the intracellular trafficking and activation of IGF-1R is unknown.…”