Correlation of Reduction in MRP-1/CD9 and KAI1/CD82 Expression with Recurrences in Breast Cancer Patients

Huang, Cheng‐Long; Kohno, Nobuoki; Ogawa, Eiji; Adachi, Masashi; Taki, Toshihiko; Miyake, Masayuki

doi:10.1016/s0002-9440(10)65639-8

Cited by 164 publications

(121 citation statements)

References 37 publications

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“…Ubiquitous expression of CD82 prompted others to explore the possibility that loss of expression may not be limited to the prostate. Loss or low expression has been shown to correlate with poor prognosis in lung (Adachi et al, 1996), pancreatic (Guo et al, 1996), breast (Huang et al, 1998), bladder (Yu et al, 1997), colon (Lombardi et al, 1999), esophageal (Uchida et al, 1999;Miyazaki et al, 2000), cervical (Liu et al, 2001), ovarian , and endometrial cancers. Downregulation of CD82 expression has also been observed in many metastatic tumor cell lines (White et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Tetraspanin KAI1/CD82 suppresses invasion by inhibiting integrin-dependent crosstalk with c-Met receptor and Src kinases

2005

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KAI1/CD82, a tetraspanin protein, was first identified as a metastasis suppressor in prostate cancer. How loss of CD82 expression promotes cancer metastasis is unknown. Restoration of CD82 expression to physiological levels in the metastatic prostate cell line PC3 inhibits integrinmediated cell migration and invasion, but does not affect integrin expression. Integrin-dependent activation of the receptor kinase c-Met is dramatically reduced in CD82-expressing cells, as is c-Met activation by its ligand HGF/ SF. CD82 expression also reduced integrin-induced activation and phosphorylation of the cytoplasmic tyrosine kinase Src, and its downstream substrates p130Cas and FAK Y861. Inhibition of c-Met expression or Src kinase function reduced matrigel invasion of PC3 cells to the same extent as CD82 expression. These data indicate that CD82 functions to suppress integrin-induced invasion by regulating signaling to c-Met and Src kinases, and suggests that CD82 loss may promote metastasis by removing a negative regulator of c-Met and Src signaling.

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Section: Introductionmentioning

confidence: 99%

Tetraspanin KAI1/CD82 suppresses invasion by inhibiting integrin-dependent crosstalk with c-Met receptor and Src kinases

2005

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“…10 Loss of KAI1 expression is also associated with a poor prognosis in several cancer types 6,11,12 and breast cancer recurrence. 13 The role of KAI1 in prostate cancer progression has been studied by several groups; indeed KAI1 was initially proposed to be a prostate-specific metastasis suppressor. 1 While recent studies have provided some evidence that increased KAI1 expression might occur in early stage disease, 14 all studies thus far have shown that KAI1 mRNA and protein levels are dramatically reduced in advanced disease, as well as in lymph node metastases.…”

Section: Introductionmentioning

confidence: 99%

Downregulation of KAI1 mRNA in localised prostate cancer and its bony metastases does not correlate with p53 overexpression

Jackson

Yardley

et al. 2003

Prostate Cancer Prostatic Dis

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Recent data have proposed that transcription of the KAI1 metastasis suppressor gene is directly mediated by p53 and that loss of KAI1 expression in advanced prostate cancer is simply due to loss of p53 function after mutation. To investigate this possibility, we have examined KAI1 mRNA (by in situ hybridisation) and p53 protein expression (by immunohistochemistry) as an indicator of wildtype or mutant p53, in a series of 77 paraffin-embedded prostate tissue samples, including post-mortem normal prostates (2), benign prostatic hyperplasia (10), localised cancer (grades 4-6, 25; grades 7-9, 21) and prostate-derived bony metastases (19). Overall, we confirmed that expression of KAI1 mRNA decreased from normal tissue, through localised cancer to bony metastases (P ¼ 0.055, tending to significance), while levels of p53 staining significantly increased with cancer progression (P ¼ 0.046). These were consistent with the possibility that loss of p53 function might be responsible for loss of KAI1 mRNA. However, by close examination of KAI1 and p53 in adjacent tissue sections, we found no correlation between decreased levels of KAI1 mRNA and overexpression of p53 protein (P ¼ 0.497). In addition, high levels of KAI1 mRNA could be identified in samples irrespective of p53 staining. Our data suggest that mutation of p53 is independent of the loss of KAI1 mRNA, and do not support a role for p53 in regulating the expression of KAI1.

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“…All of them were based on immunohistochemical analyses of a limited number of frozen breast cancer sections, because anti-KAI1 antibodies available at that time were not suitable for detection of KAI1 in larger series of formalin-fixed paraffin-embedded archival breast cancer tissue. 15,16 In addition, a number of studies concerning expression and function of KAI1 in breast cancer have been invalidated by the use of the misidentified cell line MDA-MB-435. 10,17,18 These cells have recently turned out to be M14 melanoma cells and are not informative on the biology of breast cancer.…”

mentioning

confidence: 99%

KAI1/CD82 is a novel target of estrogen receptor‐mediated gene repression and downregulated in primary human breast cancer

Christgen¹,

Bruchhardt²,

Ballmaier³

et al. 2008

Intl Journal of Cancer

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The cell-surface glycoprotein KAI1 suppresses tumor growth and metastasis in various animal models. Downregulation of KAI1 has been implicated in the progression of cancer. However, the mechanisms of KAI1 inactivation are poorly understood. This is the first study that investigates expression and regulation of KAI1 in human breast cancer. KAI1 expression was analyzed on custommade tissue microarrays comprising 209 well-characterized breast cancers and normal mammary gland tissue. Strong KAI1 immunoreactivity was observed throughout the normal mammary gland epithelium. In breast cancer tissue, KAI1 immunoreactivity was lost in 161/209 (77%) cases. Strikingly, KAI1 was preferentially lost in estrogen receptor (ER)-positive breast cancers (p < 0.001). This was validated by real-time RT-PCR analyses showing a 7.5-fold downregulation of KAI1 mRNA in ER-positive relative to ERnegative tumors (p 5 0.028). Notably, this was also corroborated by Affymetrix microarray expression data of an independent cohort of 49 breast cancers. Class comparison analysis identified KAI1 as downregulated in ER-positive tumors. Subsequently, human breast cancer cell lines were employed to test a potential role of ER-activity in the downregulation of KAI1, as suggested by our expression analyses. Exposure of ER-positive breast cancer cells to fulvestrant, a clinically approved ER-antagonist that reverses ER-mediated gene repression, induced a significant upregulation of KAI1 and inhibited cell proliferation as well as migration. In summary, we demonstrate for the first time that KAI1 is a target of ER-mediated gene-repression, and thus, it is downregulated in ER-positive breast cancer. Importantly, KAI1 might be reinducible by endocrine therapy with ER-antagonists in patients suffering from ER-positive breast cancer. ' 2008 Wiley-Liss, Inc.Key words: KAI1; breast cancer; fulvestrant; faslodex; microarray KAI1, also known as CD82, is a member of the tetraspanin or transmembrane 4 superfamily (TM4SF) of cell-surface glycoproteins. TM4SF proteins are involved in fundamental cellular processes, such as cell-cell interaction, cell motility and proliferation. 1 KAI1 is expressed by epithelial cells and is gradually downregulated or lost in prostate cancer. [2][3][4] Ectopic expression of KAI1 suppresses the metastatic phenotype of AT6.1 and LNCaP prostate cancer cells and of B16BL6 melanoma cells in experimental animal models. [5][6][7] In line with this, human prostate cancer and melanoma cell lines of metastatic origin lack expression of KAI1. 8 Therefore, KAI1 is widely perceived as a metastasis suppressor and has been suggested to represent a promising biomarker for the metastatic potential in human malignancies. 9,10 Yet, several lines of evidence indicate that KAI1 also functions as a suppressor of primary tumor growth. 11 Reestablishment of KAI1 expression in KAI1-negative cancer cells tremendously impairs tumor formation at the injection site in nude mice. 11 In addition, downregulation of KAI1 in prostate cancer is already evident in pr...

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Correlation of Reduction in MRP-1/CD9 and KAI1/CD82 Expression with Recurrences in Breast Cancer Patients

Cited by 164 publications

References 37 publications

Tetraspanin KAI1/CD82 suppresses invasion by inhibiting integrin-dependent crosstalk with c-Met receptor and Src kinases

Tetraspanin KAI1/CD82 suppresses invasion by inhibiting integrin-dependent crosstalk with c-Met receptor and Src kinases

Downregulation of KAI1 mRNA in localised prostate cancer and its bony metastases does not correlate with p53 overexpression

KAI1/CD82 is a novel target of estrogen receptor‐mediated gene repression and downregulated in primary human breast cancer

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