Autocrine laminin-5 ligates α6β4 integrin and activates RAC and NFκB to mediate anchorage-independent survival of mammary tumors

Department of Pathology and Laboratory Medicine, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
The Journal of Cell Biology (Impact Factor: 9.69). 01/2004; 163(6):1397-407. DOI: 10.1083/jcb.200302023
Source: PubMed

ABSTRACT Invasive carcinomas survive and evade apoptosis despite the absence of an exogenous basement membrane. How epithelial tumors acquire anchorage independence for survival remains poorly defined. Epithelial tumors often secrete abundant amounts of the extracellular matrix protein laminin 5 (LM-5) and frequently express alpha6beta4 integrin. Here, we show that autocrine LM-5 mediates anchorage-independent survival in breast tumors through ligation of a wild-type, but not a cytoplasmic tail-truncated alpha6beta4 integrin. alpha6beta4 integrin does not mediate tumor survival through activation of ERK or AKT. Instead, the cytoplasmic tail of beta4 integrin is necessary for basal and epidermal growth factor-induced RAC activity, and RAC mediates tumor survival. Indeed, a constitutively active RAC sustains the viability of mammary tumors lacking functional beta1 and beta4 integrin through activation of NFkappaB, and overexpression of NFkappaB p65 mediates anchorage-independent survival of nonmalignant mammary epithelial cells. Therefore, epithelial tumors could survive in the absence of exogenous basement membrane through autocrine LM-5-alpha6beta4 integrin-RAC-NFkappaB signaling.

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Available from: Valerie M Weaver, Aug 13, 2015
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    • "Based on the association of a 6 b 4 integrin in mammary tumourigenesis (Shaw et al, 1997; Zahir et al, 2003; Guo et al, 2006), the relevance of CD151 in breast cancer was also hypothesised. Indeed, Yang et al (2008) showed that CD151 expression is elevated in breast cancer, with even more upregulation in high-grade and oestrogennegative subtypes including basal-like breast cancer. "
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    • "In this regard, there is extensive evidence that matrix receptors are modulated by cell and tissue context. For example, in keratinocytes, α6β4 integrin, a receptor for LM332, retards migration when incorporated into hemidesmosomal adhesions but activates pathways that support cell migration in motile cells during tumorigenesis and wound healing (Pullar et al., 2006; Rabinovitz et al., 1999; Sehgal et al., 2006; Shaw et al., 1997; Xia et al., 1996; Zahir et al., 2003). A similar situation may also exist for a second LM332 receptor, namely α3β1 integrin, since there are reports that it functions as both a positive and negative regulator of keratinocyte migration (Hodivala-Dilke et al., 1998; Margadant et al., 2009; Reynolds et al., 2008; Wen et al., 2010). "
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    • "Recent studies have determined that the effectors of Ral GTPases have been implicated in vesicle transport (Camonis and White, 2005; Rosse et al., 2006), endocytosis (Jullien-Flores et al., 2000), gene transcription (Frankel et al., 2005), development of filopodia (Ohta et al., 1999) and cellular proliferation (Smith et al., 2006). In addition to these effectors, recent research has determined that improper activation of Ral GTPases has been implicated in oncogenesis through its role in metastasis (Lim et al., 2005; Lim et al., 2006; Oxford and Theodorescu, 2003), resistance to anoikis (Zahir et al., 2003), activation of transcription factors (Frankel et al., 2005) and inappropriate cell survival signals (Chien et al., 2006; Smith et al., 2006). "
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