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Expression of AMAP1, an ArfGAP, provides novel targets to inhibit breast cancer invasive activities.

ABSTRACT: Identification of the molecular machinery employed in cancer invasion, but not in normal adult cells, will greatly contribute to cancer therapeutics. Here we found that an ArfGAP, AMAP1/PAG2, is expressed at high levels in highly invasive breast cancer cells, but at very low levels in noninvasive breast cancer cells and normal mammary epithelial cells. siRNA-mediated silencing of AMAP1 effectively blocked the invasive activities. AMAP1 expression in human breast primary tumors also indicated its potential correlation with malignancy. Paxillin and cortactin have been shown to colocalize at invadopodia and play a pivotal role in breast cancer invasion. We found that AMAP1 is also localized at invadopodia, and acts to bridge paxillin and cortactin. This AMAP1-mediated trimeric protein complex was detected only in invasive cancer cells, and blocking this complex formation effectively inhibited their invasive activities in vitro and metastasis in mice. Our results indicate that AMAP1 is a component involved in invasive activities of different breast cancers, and provide new information regarding the possible therapeutic targets for prevention of breast cancer invasion and metastasis.

SUBMITTER: Onodera Y

PROVIDER: S-EPMC554134 | biostudies-literature | 2005 Mar

REPOSITORIES: biostudies-literature

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Expression of AMAP1, an ArfGAP, provides novel targets to inhibit breast cancer invasive activities.

Onodera Yasuhito Y Hashimoto Shigeru S Hashimoto Ari A Morishige Masaki M Mazaki Yuichi Y Yamada Atsuko A Ogawa Eiji E Adachi Masashi M Sakurai Takaki T Manabe Toshiaki T Wada Hiromi H Matsuura Nariaki N Sabe Hisataka H

The EMBO journal 20050217 5

Identification of the molecular machinery employed in cancer invasion, but not in normal adult cells, will greatly contribute to cancer therapeutics. Here we found that an ArfGAP, AMAP1/PAG2, is expressed at high levels in highly invasive breast cancer cells, but at very low levels in noninvasive breast cancer cells and normal mammary epithelial cells. siRNA-mediated silencing of AMAP1 effectively blocked the invasive activities. AMAP1 expression in human breast primary tumors also indicated its ...[more]

PMID: 15719014

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Project description:Introduction: microRNAs (miRNAs) are short non-coding RNAs that negatively regulate gene expression and may play a causal role in invasive breast cancer. Since many genetic aberrations of invasive disease are detectable in earlier stages, we hypothesized that miRNA expression dysregulation and the predicted changes in gene expression would also be found in early breast neoplasias. Methods: Expression profiling of 365 miRNAs by RT-qPCR was combined with laser-capture microdissection to obtain an epithelial specific miRNA expression signature of normal breast epithelium (n=9) and of paired samples of histologically normal epithelium (HN) and ductal carcinoma in situ (DCIS) (n=16). To determine how miRNAs may control the expression of co-dysregulated mRNAs we also performed gene expression microarray analysis in the same paired HN and DCIS samples and integrated this with miRNA-target prediction. We further validated several target pairs by modulating the expression levels of miRNAs in MCF7 cells and measured the expression of target mRNAs and proteins. Results: Thirty-five miRNAs were aberrantly expressed between RM, HN and DCIS. Twenty-nine miRNAs and 420 mRNAs were aberrantly expressed between HN and DCIS. Combining these two datasets with miRNA-target prediction we identified two established target pairs (miR-195:CCND1 and miR-21:NFIB) and tested several novel miRNA:mRNA target pairs. Over-expression of the putative tumor-suppressor miR-125b, under-expressed in DCIS, repressed the expression of MEMO1, which is required for ErbB2-driven cell motility (also a target of miR-125b); and NRIP1/RIP140, which modulates the transcriptional activity of the estrogen receptor. Knockdown of the putative oncogenic miRNAs miR-182 and miR-183, both highly over-expressed in DCIS, increased the expression of CBX7 (which regulates E-cadherin expression), DOK4, NMT2, and EGR1. Augmentation of CBX7 by knockdown of miR-182 expression, in turn, positively regulated the expression of E-cadherin, a key protein involved in maintaining normal epithelial cell morphology which is commonly lost during neoplastic progression. Conclusions: These data provide the first miRNA expression profile of normal breast epithelium and of pre-invasive breast carcinoma. Further, we demonstrate that altered miRNA expression can modulate gene expression changes that characterize these early cancers. We conclude that miRNA dysregulation likely plays a substantial role in early breast cancer development. Two total samples were analyzed via Affymetrix U133A. Case numbers correspond to individual patients. Each sample is identified by case number, histologic lesion and corresponding microarray ID.

Project description:BackgroundVarious features extracted from breast MRI have the potential to serve as noninvasive biomarkers for the prediction of the biologic behavior of breast cancer. The purpose of this study was to investigate the value of focal breast edema and breast edema score (BES) on T2-weighted images in providing valuable biological information for breast cancer patients' personalized treatment.MethodTwo hundred and five lesions in 201 patients with invasive breast cancer confirmed by surgery or biopsy in Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine from November 2018 to October 2019 were retrospectively recruited and analyzed in this study. Focal edema and BES were evaluated at fat-suppressed T2 weighted imaging. All the lesions were divided into two groups according to the presence of focal edema. The differences in clinicopathological characteristics between the two groups and between different BES were compared.ResultsTwo hundred and five lesions in 201 patients with invasive breast cancer were retrospectively recruited and analyzed in this study. On the fat-suppressed T2WI, focal edema was detected in 102 of 205 lesions (49.8%). BES was positively correlated with tumor size (p < 0.001), histologic grade (p = 0.006), Ki-67 index (p < 0.001), and N stage (p = 0.007), and was negatively correlated with expression of ER and PR (p < 0.001). Higher BES was more likely to present in patients with non-luminal breast cancer (p < 0.001) and suggested the possibility of a higher N stage.ConclusionsFocal edema on T2WI of breast MRI indicates stronger tumor invasiveness, in which non-luminal breast cancer is more inclined to present focal edema. Breast edema score, a novel and practical tool, helps guide the individualized treatment of patients with invasive breast cancer.Critical relevance statementFocal edema on T2WI of breast MRI indicates stronger tumor invasiveness. Breast edema score helps guide the individualized treatment of patients with invasive breast cancer.

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Expression of AMAP1, an ArfGAP, provides novel targets to inhibit breast cancer invasive activities.

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Expression of AMAP1, an ArfGAP, provides novel targets to inhibit breast cancer invasive activities.

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