Integrin activation controls metastasis in human breast cancer

Felding-Habermann, Brunhilde; O’Toole, Timothy E.; Smith, Jeffrey W.; Fransvea, Emilia; Ruggeri, Zaverio M.; Ginsberg, Mark H.; Hughes, Paul E.; Pampori, Nisar A.; Shattil, Sanford J.; Saven, Alan; Mueller, Barbara M.

doi:10.1073/pnas.98.4.1853

Cited by 516 publications

(463 citation statements)

References 29 publications

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“…40,45 In breast, ␣v␤3 characterizes the metastatic phenotype as this integrin is upregulated in invasive tumors and in distant metastases. 45,46 Thus, the pattern of integrin expression in the tumor cell is implicated in the enhanced proliferation that is a characteristic of tumor cells. The data we have obtained with the MDA-MB-435 cells are consistent with a role for ILK in the modulation of integrin expression and integrin-regulated cellular proliferation.…”

Section: Growth-inhibitory Functions Of Ilkmentioning

confidence: 99%

Suppression of malignant growth of human breast cancer cells by ectopic expression of integrin‐linked kinase

Chen

Shen

Karnik

2004

Intl Journal of Cancer

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Allelic loss at the short arm of chromosome 11 is one of the most common and potent events in the progression and metastasis of breast cancer. Here, we present evidence that the Integrin-Linked Kinase (ILK) gene maps to the commonly deleted chromosome 11p15. Genetic alterations that occur in breast cancer are believed to be of importance for initiation as well as progression of the disease. These genetic alterations lead to the loss or activation of a number of critical genes, such as those involved in cell proliferation, differentiation, apoptosis and genetic stability. The genetic abnormalities most frequently observed in breast tumors are amplification of proto-oncogenes (MYC, ERBB2 and CCND1), mutations of TP53 and loss of heterozygosity (LOH) on chromosomes 3p, 6q, 7q, 8p, 9p, 11, 13q, 17, 18q and 22q. 1,2 Metastatic phenotypes have been linked to such genes as NME1 (17q), CDH1 (16q), BRMS1 (11q) and KISS1 (1q). 1,3-5 LOH analyses have defined regions of deletion associated with metastasis on chromosomes 3p21, 15q14, 16q22 and 11p15. 2,6 Frequent genetic alterations on chromosome 11p15 suggest a crucial role for this region in breast 6,7 and other adult 8 -12 and childhood cancers. [13][14][15][16][17] More recently, we have mapped 2 distinct regions on chromosome 11p15.5 that are subject to LOH during breast tumor progression and metastasis. 6 LOH at region 1 correlated with tumors that contain ductal carcinoma in situ, suggesting that the loss of a critical gene in this region may be responsible for early events in malignancy. LOH at region 2 correlated with a more aggressive tumor and an ominous outlook for the patient, such as aneuploidy, high S-phase fraction and the presence of metastasis in regional lymph nodes. Although considerable advances have been made in the fine-mapping of chromosome 11p15.5, the tumor/metastasis suppressor gene(s) encoded by this region has evaded identification.Integrin-linked kinase (ILK) is an intriguing serine/threonine kinase that has been implicated in integrin-, growth-factor-and Wnt-signaling pathways. 18 It binds to the cytoplasmic domains of ␤1 and ␤3 integrins and mediates the downstream signaling events in integrin function. 19 Interactions between integrins and their ligands are involved in the regulation of many cellular functions, including embryonic development, cell proliferation, tumor growth and the ability to metastasize. 20 In Drosophila, the absence of ILK function causes defects similar to loss of integrin adhesion, and ILK mutations cause embryonic lethality and defects in muscle attachment. 21 Although ILK maps to the commonly deleted chromosome 11p, the potential of this gene in tumor/metastasis suppression has not been evaluated. We have therefore analyzed the effect of ILK expression on the in vitro and in vivo tumor growth and invasion of human mammary carcinoma cells. MATERIAL AND METHODS Mapping of ILK to LOH region 2Two YAC clones (847a12 and 696H10), a BAC clone (BAC 1760) and a PAC clone (PAC1331) overlapped the LOH region 2 and were used to...

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Section: Growth-inhibitory Functions Of Ilkmentioning

confidence: 99%

Suppression of malignant growth of human breast cancer cells by ectopic expression of integrin‐linked kinase

Chen

Shen

Karnik

2004

Intl Journal of Cancer

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“…Integrin activation has been shown to have a seminal role in the development and progression of breast cancer, which is achieved through intracellular signaling by the activation of downstream kinases such as MAPK (Taddei et al, 2003;Vellon et al, 2005). Overexpression of CCN1 in breast cancer cells culminates in upregulation of MAPK and other cell-proliferation signals in an integrin avb3-dependent manner, thereby promoting cell survival and chemoresistance to therapeutic agents (Felding-Habermann et al, 2001;Menendez et al, 2005). The CCN1 gene encodes a 42-kDa matricellular protein that belongs to the CCN gene family (Brigstock, 1999;Grotendorst et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of AP-1 by SARI negatively regulates transformation progression mediated by CCN1

Dash

Lee

et al. 2010

Oncogene

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Enhanced expression of the CCN family of secretory integrin-binding proteins correlates with many essential components of the cancerous state, including tumor cell adhesion, proliferation, invasion and migration. Consequently, CCN1 expression is elevated in various cancers, including breast cancer, and its expression directly correlates with poor patient prognosis. Using subtraction-hybridization, combined with induction of cancer cell terminal differentiation, we cloned SARI (suppressor of activator protein (AP)-1, regulated by interferon (IFN)), an IFN-b-inducible, potent tumor suppressor gene that exerts cancer-selective growth inhibitory effects. Forced expression of SARI using an adenovirus (Ad.SARI) inhibits AP-1 function and downregulates CCN1 expression in multiple cancer lineages, resulting in a profound inhibition in anchorage-independent cell growth and tumor cell invasion. Overexpression of SARI reduces CCN1-promoter activity through inhibition of AP-1 binding. Accordingly, SARI selectively blocks expression of the transformed state in rat embryo fibroblast cells that stably overexpress c-Jun. These results illustrate that SARI inhibits AP-1 transactivating factor binding to the ciselement of the CCN1 promoter, possibly through its interaction with c-Jun. Overall, SARI can directly inhibit CCN1-induced transformation by inhibiting the transcription of CCN1, as well as indirectly by inhibiting the expression of c-Jun (and hence blocking AP-1 activity). In these contexts, transformed cells 'addicted' to AP-1 activity are rendered susceptible to SARI-mediated inhibition of expression of the transformed phenotype.

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“…In addition, during dynamic and complex processes, such as organ development and tumor progression and metastasis, the cellular distribution and/or intensity of expression may change (Arroyo et al, 2000;Boudreau and Jones, 1999;Brown, 2000;Coraux et al, 1998;Dedhar and Hannigan, 1996;Felding-Habermann et al, 2001;Frisch and Ruoslahti, 1997;Giancotti, 1997;Hemler, 1998;Howe et al, 1998;Hynes, 1992;Ingber, 1991;Legier et al, 2001;Schwartz, 1997;Shyy and Chien, 1997).…”

Section: Introductionmentioning

confidence: 99%

Integrin characterization in pulmonary bronchioles

Blundell

Harrison

2005

Experimental and Molecular Pathology

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Integrins are a family of cell surface glycoproteins that act as receptors for ECM proteins or for membrane bound counter-receptors on other cells. The integrin receptor family of vertebrates includes at least 16 distinct a subunits and at least 8 h subunits which can associate to form more than 20 distinct integrins. So far, there are no published reports describing integrin characterization in mouse lung tissue and mouse Clara cells. This paper described the characterization of six integrins, mainly a 5 , a v , a 6 , h 1 , h 3 , and h 4 , in mouse pulmonary bronchioles and also in Clara cell cultures. a 5 , a v , a 6 , h 1 , and h 4 integrins were present in Clara cells both in tissue sections and cultures. h 3 integrin was found to be absent in mouse Clara cells.

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Integrin activation controls metastasis in human breast cancer

Cited by 516 publications

References 29 publications

Suppression of malignant growth of human breast cancer cells by ectopic expression of integrin‐linked kinase

Suppression of malignant growth of human breast cancer cells by ectopic expression of integrin‐linked kinase

Inhibition of AP-1 by SARI negatively regulates transformation progression mediated by CCN1

Integrin characterization in pulmonary bronchioles

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