Autocrine laminin-5 ligates α6β4 integrin and activates RAC and NFκB to mediate anchorage-independent survival of mammary tumors
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.
Full-textDOI: · Available from: Valerie M Weaver, Aug 13, 2015
- SourceAvailable from: Young Kee Shin
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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. "
ABSTRACT: CD151 is a member of the tetraspanin family, which interacts with laminin-binding integrins and other tetraspanins. This protein is implicated in motility, invasion, and metastasis of cancer cells, but the prevalence of CD151 expression in subtypes of breast cancers and its influence on clinical outcome remains to be evaluated. The immunohistochemistry-based tissue microarray analysis showed that 127 (14.3%) cases overexpressed CD151 among 886 breast cancer patients. CD151 overexpression was found to be significantly associated with larger tumour size, higher nodal stage, advanced stage, absence of oestrogen receptor and progesterone receptor, and human epidermal growth factor receptor 2 overexpression. CD151 overexpression resulted in poorer overall survival (OS) (P<0.001) and disease-free survival (P=0.02), and stage II and III patients with CD151 overexpression demonstrated substantially poorer OS (P=0.0474 and 0.0169). In the five subtypes analyses, CD151 overexpression retained its adverse impact on OS in the Luminal A (P=0.0105) and quintuple-negative breast cancer (QNBC) subtypes, one subgroup of triple-negative breast cancer (P=0.0170). Multivariate analysis that included stage, subtype, and adjuvant chemotherapy showed that CD151 overexpression was independently associated with poor OS in invasive breast cancer. CD151 overexpression may be a potential molecular therapeutic target for breast cancer, especially in QNBC subtype and more advanced stages of breast cancer.British Journal of Cancer 02/2012; 106(5):923-30. DOI:10.1038/bjc.2012.11 · 4.82 Impact Factor
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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). "
ABSTRACT: Mouse keratinocytes migrate significantly slower than their human counterparts in vitro on uncoated surfaces. We tested the hypothesis that this is a consequence of differences in the extracellular matrix (ECM) that cells deposit. In support of this, human keratinocyte motility was markedly reduced when plated onto the ECM of mouse skin cells, whereas the latter cells migrated faster when plated onto human keratinocyte ECM. The ECM of mouse and human keratinocytes contained similar levels of the α3 laminin subunit of laminin-332. However, mouse skin cells expressed significantly more fibronectin (FN) than human cells. To assess whether FN is a motility regulator, we used small interfering RNA (siRNA) to reduce the expression of FN in mouse keratinocytes. The treated mouse keratinocytes moved significantly more rapidly than wild-type mouse skin cells. Moreover, the FN-depleted mouse cell ECM supported increased migration of both mouse and human keratinocytes. Furthermore, the motility of human keratinocytes was slowed when plated onto FN-coated substrates or human keratinocyte ECM supplemented with FN in a dose-dependent manner. Consistent with these findings, the ECM of α3 integrin-null keratinocytes, which also migrated faster than wild-type cells, was FN deficient. Our results provide evidence that FN is a brake to skin cell migration supported by laminin-332-rich matrices.Journal of Investigative Dermatology 09/2011; 132(2):448-57. DOI:10.1038/jid.2011.297 · 6.37 Impact Factor
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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). "
ABSTRACT: The Ras superfamily of GTPases is involved in the modification of many cellular processes including cellular motility, proliferation and differentiation. Our laboratory has previously identified the RalGDS-related (Rgr) oncogene in a DMBA (7,12-dimethylbenz[α]anthracene)-induced rabbit squamous cell carcinoma and its human orthologue, hRgr. In this study, we analyzed the expression levels of the human hRgr transcript in a panel of human hematopoietic malignancies and found that a truncated form (diseased-truncated (Dtr-hrgr)) was significantly overexpressed in many T-cell-derived neoplasms. Although the Rgr proto-oncogene belongs to the RalGDS family of guanine nucleotide exchange factors (GEFs), we show that upon the introduction of hRgr into fibroblast cell lines, it is able to elicit the activation of both Ral and Ras GTPases. Moreover, in vitro guanine nucleotide exchange assays confirm that hRgr promotes Ral and Ras activation through GDP dissociation, which is a critical characteristic of GEF proteins. hRgr has guanine nucleotide exchange activity for both small GTPases and this activity was reduced when a point mutation within the catalytic domain (CDC25) of the protein, (cd) Dtr-hRgr, was utilized. These observations prompted the analysis of the biological effects of hRgr and (cd) hRgr expression in cultured cells. Here, we show that hRgr increases proliferation in low serum, increases invasion, reduces anchorage dependence and promotes the progression into the S phase of the cell cycle; properties that are abolished or severely reduced in the presence of the catalytic dead mutant. We conclude that the ability of hRgr to activate both Ral and Ras is responsible for its transformation-inducing phenotype and it could be an important contributor in the development of some T-cell malignancies.Oncogene 03/2011; 30(34):3661-71. DOI:10.1038/onc.2011.93 · 8.56 Impact Factor