Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0006142 (breast cancer)
 160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Micropapillary carcinomas (MPCs) can present as a rare histological special type of breast cancer; however, this histological type is more frequently found admixed with invasive ductal carcinomas of no special type (IDC-NSTs). We have previously demonstrated that pure MPCs constitute a distinct entity at the morphological and genetic levels. Here, we sought to determine whether mixed MPCs have genomic aberrations similar to those found in pure MPCs, and to investigate whether the distinct morphological components of MPCs harbour different genetic aberrations. Using high-resolution microarray comparative genomic hybridization (aCGH), we profiled a series of 10 MPCs of mixed histology and 20 IDC-NSTs matched for grade and oestrogen receptor (ER) status. In addition, we generated tissue microarrays containing a series of 24 pure and 40 mixed MPCs and performed immunohistochemical analysis with ER, progesterone receptor (PR), Ki-67, HER2, cytokeratin (CK) 5/6, CK14, CK17, EGFR, topoisomerase-IIalpha, cyclin D1, caveolin-1 and E-cadherin antibodies. In situ hybridization was employed to evaluate the prevalence of HER2, TOP2A, EGFR, CCND1, MYC and FGFR1 gene amplification. Our results demonstrate that mixed MPCs harbour similar patterns of genomic aberrations and phenotype (82.5% luminal and 17.5% HER2) compared to pure MPCs. A comparison between the distinct morphological components of mixed MPCs in a pairwise fashion revealed that both components harbour strikingly similar genomic profiles. When compared to grade- and ER-matched IDC-NSTs, mixed MPCs significantly more frequently harboured amplification of multiple regions on 8q (adjusted Fisher's p value < 0.05). Furthermore, mixed MPCs displayed higher proliferative rates than grade- and ER-matched IDC-NSTs. Our results suggest that micropapillary differentiation in breast cancer may identify a subgroup of more aggressive ER-positive breast carcinomas, even in those featuring a mixed histology, and that mixed MPCs are more closely related to pure MPCs than to IDC-NSTs.
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PMID:Mixed micropapillary-ductal carcinomas of the breast: a genomic and immunohistochemical analysis of morphologically distinct components. 1947 27

Enhanced RAS signaling and decreased androgen dependence of prostate cancer cells accompany poor clinical outcomes. Elevated autocrine fibroblast growth factors 2 (FGF-2) signaling promotes prostate cancer cell growth and survival. Expression of lysyl oxidase (LOX) inhibits RAS transforming activity. LOX is secreted as 50 kDa pro-LOX protein and then undergoes extracellular proteolytic processing to form approximately 30 kDa LOX enzyme and approximately 18 kDa propeptide (LOX-PP). We have previously shown that LOX-PP inhibits breast cancer cell transformation and tumor formation, but mechanisms of action of LOX-PP have not been fully elucidated. Here we report that LOX expression is reduced in prostate cancer cell lines and that recombinant LOX-PP protein inhibits serum-stimulated DNA synthesis and MEK/ERK and PI3K/AKT pathways in DU 145 and PC-3 androgen-independent cell lines. In DU 145 cells, treatment with a pharmacologic FGF-receptor inhibitor or a neutralizing anti-FGFR1 antibody mimicked LOX-PP inhibition of serum-stimulated DNA synthesis. FGF-2-stimulated DNA synthesis, ERK1/2, AKT and FRS2alpha activation were found all to be inhibited by LOX-PP in DU 145 cells. LOX-PP reduced specific binding of FGF-2 to DU 145 cells, suggesting that LOX-PP targets FGF signaling at the receptor. Interestingly, PC-3 cells did not respond to FGF-2, consistent with previous reports. We conclude that LOX-PP inhibits proliferation of DU 145 cells by interfering with FGFR(s) binding and signaling, and that LOX-PP has other mechanisms of action in PC-3 cells.
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PMID:Lysyl oxidase propeptide inhibits prostate cancer cell growth by mechanisms that target FGF-2-cell binding and signaling. 1959 71

The fibroblast growth factor (FGF) family is comprised of 22 ligands that bind and activate several FGF receptor (FGFR) isoforms. Critical roles for FGFs and FGFRs have been well-established during embryonic development. For example, the FGF10/FGFR2IIIb axis has been linked to embryonic development of both the mammary and prostate glands, which are the subject of this review. Furthermore, recent studies using novel mouse models have suggested that this pathway also participates in postnatal development in the mammary and prostate glands. These studies have provided novel insights into the mechanisms by which FGFs and FGFRs promote ductal outgrowth and branching morphogenesis. In addition to the established roles of FGFs in development, aberrant activation of the FGF pathway has been linked to tumor progression in both breast and prostate cancer. Recent studies have linked FGFR1 expression and single nucleotide polymorphisms in FGFR2 to breast cancer. Furthermore, novel pre-clinical models have demonstrated the ability of FGFRs to promote numerous aspects of breast and prostate cancer. Understanding the roles of FGFs in development will provide insights into the mechanisms by which deregulation of the FGF pathway leads to tumorigenesis, ultimately leading to the development of novel therapeutic strategies designed to target this pathway in cancer patients.
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PMID:Fibroblast growth factors in development and cancer: insights from the mammary and prostate glands. 1960 67

To identify genetic events that characterize cancer progression, we conducted a comprehensive genetic evaluation of 161 primary breast tumors. Similar to the "mountain-and-hill" view of mutations, gene amplification also shows high- and low-frequency alterations in breast cancers. The frequently amplified genes include the well-known oncogenes ERBB2, FGFR1, MYC, CCND1, and PIK3CA, whereas other known oncogenes that are amplified, although less frequently, include CCND2, EGFR, FGFR2, and NOTCH3. More importantly, by honing in on minimally amplified regions containing three or fewer genes, we identified six new amplified genes: POLD3, IRAK4, IRX2, TBL1XR1, ASPH, and BRD4. We found that both the IRX2 and TBL1XR1 proteins showed higher expression in the malignant cell lines MCF10CA1h and MCF10CA1a than in their precursor, MCF10A, a normal immortalized mammary epithelial cell line. To study oncogenic roles of TBL1XR1, we performed knockdown experiments using a short hairpin RNA approach and found that depletion of TBL1XR1 in MCF10CA1h cells resulted in reduction of cell migration and invasion as well as suppression of tumorigenesis in mouse xenografts. Intriguingly, our mutation analysis showed the presence of activation mutations in the PIK3CA gene in a subset of tumors that also had DNA copy number increases in the PIK3CA locus, suggesting an additive effect of coexisting activating amino acid substitution and dosage increase from amplification. Our gene amplification and somatic mutation analysis of breast primary tumors provides a coherent picture of genetic events, both corroborating and novel, offering insight into the genetic underpinnings of breast cancer progression.
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PMID:Identification of novel gene amplifications in breast cancer and coexistence of gene amplification with an activating mutation of PIK3CA. 1970 70

Saethre-Chotzen syndrome is one of the most common craniosynostosis syndromes. It is an autosomal dominantly inherited disorder with variable expression that is caused by germline mutations in the TWIST1 gene or more rarely in the FGFR2 or FGFR3 genes. We have previously reported that patients with Saethre-Chotzen syndrome have an increased risk of developing breast cancer. Here we have analysed a cohort of 26 women with BRCA1/2-negative hereditary breast cancer to study whether a proportion of these families might have mutations in Saethre-Chotzen-associated genes. DNA sequence analysis of TWIST1 showed no pathogenic mutations in the coding sequence in any of the 26 patients. MLPA (multiplex ligation-dependent probe amplification)-analysis also showed no alterations in copy numbers in any of the craniofacial disorder genes MSX2, ALX4, RUNX2, EFNB1, TWIST1, FGFR1, FGFR2,FGFR3, or FGFR4. Taken together, our findings indicate that mutations in Saethre-Chotzen-associated genes are uncommon or absent in BRCA1/2-negative patients with hereditary breast cancer.
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PMID:Germline mutation screening of the Saethre-Chotzen-associated genes TWIST1 and FGFR3 in families with BRCA1/2-negative breast cancer. 1986 27

Several oncogenes and tumor-suppressor genes have been shown to be implicated in the development, progression and response to therapy of invasive breast cancer. The phenotypic uniqueness (and thus the heterogeneity of clinical behavior) among patients' tumors may be traceable to the underlying variation in gene copy number of these genes. To obtain a more complete view of gene copy number changes and their relation to phenotype, we analyzed 20 breast cancer-related genes in 104 invasive breast cancers with the use of multiplex ligation-dependent probe amplification (MLPA). We identified MYC gene amplification in 48% of patients, PRDM14 in 34%, topoisomerase IIalpha (TOP2A) in 32%, ADAM9 in 32%, HER2 in 28%, cyclin D1 (CCND1) in 26%, EMSY in 25%, IKBKB in 21%, AURKA in 17%, FGFR1 in 17%, estrogen receptor alpha (ESR1) in 16%, CCNE1 in 12% and EGFR in 9% of patients. There was a significant correlation between the number of amplified genes and the histological grade and mitotic index of the tumor. Gene amplifications of EGFR, CCNE1 and HER2 were negatively associated with estrogen receptor status whereas FGFR1, ADAM9, IKBKB and TOP2A revealed a positive association. Amplifications of ESR1, PRDM14, MYC and HER2 were associated with a high mitotic index, and PRDM14 and HER2 amplifications with high histological grade. MYC amplification was detected more frequently in ductal tumors and high-level MYC amplifications were significantly associated with large tumor size. HER2/MYC, HER2/CCNE1 and EGFR/MYC co-amplified tumors were significantly larger than tumors with either of these amplifications. Gene loss occurred most frequently in E-cadherin (CDH1) (20%) and FGFR1 (10%). In conclusion, MLPA analysis with this 'breast cancer kit' allowed to simultaneously assess copy numbers of 20 important breast cancer genes, providing an overview of the most frequent (co)amplifications as well as interesting phenotypic correlations, and thereby data on the potential importance of these genes in breast cancer.
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PMID:Molecular profiling of invasive breast cancer by multiplex ligation-dependent probe amplification-based copy number analysis of tumor suppressor and oncogenes. 2047 80

Fibroblast growth factor (FGF) cooperates with the Wnt/beta-catenin pathway to promote mammary tumorigenesis. To investigate the mechanisms involved in FGF/Wnt cooperation, we genetically engineered a model of inducible FGF receptor (iFGFR) signaling in the context of the well-established mouse mammary tumor virus-Wnt-1 transgenic mouse. In the bigenic mice, iFGFR1 activation dramatically enhanced mammary tumorigenesis. Expression microarray analysis did not show transcriptional enhancement of Wnt/beta-catenin target genes but instead showed a translational gene signature that also correlated with elevated FGFR1 and FGFR2 in human breast cancer data sets. Additionally, iFGFR1 activation enhanced recruitment of RNA to polysomes, resulting in a marked increase in protein expression of several different Wnt/beta-catenin target genes. FGF pathway activation stimulated extracellular signal-regulated kinase and the phosphorylation of key translation regulators both in vivo in the mouse model and in vitro in a human breast cancer cell line. Our results suggest that cooperation of the FGF and Wnt pathways in mammary tumorigenesis is based on the activation of protein translational pathways that result in, but are not limited to, increased expression of Wnt/beta-catenin target genes (at the level of protein translation). Further, they reveal protein translation initiation factors as potential therapeutic targets for human breast cancers with alterations in FGF signaling.
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PMID:Fibroblast growth factor receptor signaling dramatically accelerates tumorigenesis and enhances oncoprotein translation in the mouse mammary tumor virus-Wnt-1 mouse model of breast cancer. 2050 44

Evaluation of: Turner N, Pearson A, Sharpe R et al. FGFR1 amplification drives endocrine therapy resistance and is a therapeutic target in breast cancer. Cancer Res. 70(5), 2085-2094 (2010). FGF receptor (FGFR) family members are aberrantly activated during carcinogenesis due to gene amplification, chromosomal translocation and missense mutation. FGFR1 is preferentially amplified in estrogen receptor-positive breast cancer, whereas FGFR2 is amplified in triple-negative breast cancer and diffuse-type gastric cancer. Gene amplification of FGFRs results in ligand-independent FGFR signaling to RAS-ERK, PI3K-AKT and JAK-STAT cascades due to the overexpression of wild-type or C-terminally deleted FGFRs. Cediranib, TKI258, Ki23057, MK-2461 and brivanib are broad-range tyrosine kinase inhibitors targeting FGFRs and other receptors. Clinical application of small-molecule FGFR inhibitors could improve the prognosis of FGFR-driven cancer patients. Diagnostic detection of tumors with FGFR genetic alterations in primary lesion, peritoneal effusion, pleural effusion and bone marrow is necessary to select patients for FGFR-targeted therapeutics.
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PMID:Genetic alterations of FGF receptors: an emerging field in clinical cancer diagnostics and therapeutics. 2017 96

Ductal carcinoma in situ (DCIS) accounts for approximately 20% of mammographically detected breast cancers. Although DCIS is generally highly curable, some women with DCIS will develop life-threatening invasive breast cancer, but the determinants of progression to infiltrating ductal cancer (IDC) are largely unknown. In the current study, we used multiplex ligation-dependent probe amplification (MLPA), a multiplex PCR-based test, to compare copy numbers of 21 breast cancer related genes between laser-microdissected DCIS and adjacent IDC lesions in 39 patients. Genes included in this study were ESR1, EGFR, FGFR1, ADAM9, IKBKB, PRDM14, MTDH, MYC, CCND1, EMSY, CDH1, TRAF4, CPD, MED1, HER2, CDC6, TOP2A, MAPT, BIRC5, CCNE1 and AURKA.There were no significant differences in copy number for the 21 genes between DCIS and adjacent IDC. Low/intermediate-grade DCIS showed on average 6 gains/amplifications versus 8 in high-grade DCIS (p=0.158). Furthermore, alterations of AURKA and CCNE1 were exclusively found in high-grade DCIS, and HER2, PRDM14 and EMSY amplification was more frequent in high-grade DCIS than in low/intermediate-grade DCIS. In contrast, the average number of alterations in low/intermediate and high-grade IDC was similar, and although EGFR alterations were exclusively found in high-grade IDC compared to low/intermediate-grade IDC, there were generally fewer differences between low/intermediate-grade and high-grade IDC than between low/intermediate-grade and high-grade DCIS.In conclusion, there were no significant differences in copy number for 21 breast cancer related genes between DCIS and adjacent IDC, indicating that DCIS is genetically as advanced as its invasive counterpart. However, high-grade DCIS showed more copy number changes than low/intermediate-grade DCIS with specifically involved genes, supporting a model in which different histological grades of DCIS are associated with distinct genomic changes that progress to IDC in different routes. These high-grade DCIS specific genes may be potential targets for treatment and/or predict progression.
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PMID:Molecular differences between ductal carcinoma in situ and adjacent invasive breast carcinoma: a multiplex ligation-dependent probe amplification study. 2154 76

Proliferation, dedifferentiation and loss of cell-cell contacts are amongst the first steps of the metastatic cascade. The complex molecular pathways and gene expression changes associated with these events in canine mammary tumors are still largely undetermined. In this study, the transcriptome of 13 lymph node positive canine mammary carcinomas and corresponding non-neoplastic mammary glands were compared to identify the molecular pathways associated with metastatic progression. Differential gene expression was analyzed using gene set enrichment and pathway analysis and compared with gene expression data from human breast cancer. Metastatic canine carcinomas had 1312 significantly differentially expressed genes compared to normal mammary glands. This expression profile included a significant up-regulation of cell division and matrix invasion genes (MMP, SERPINE1, TIMP3). In contrast, genes associated with epithelial differentiation (EGF, EGFR, MAP2K6, STAT 5), cell adhesion (CLDN5, CTNNAL1, MUC1, PECAM1) and angiogenesis (ANGPT 2, ANGPTL1-4, FIGF, TIE1) were mostly down-regulated. Tumors had a significant decrease in membrane receptors and pathway gene expression (EGFR, FGFR1, GHR, PDGFR, TGFBR, TIE1) indicating a tendency towards independence from these proliferative stimuli. A number of the identified deregulated pathways overlapped with gene expression profiles of human breast cancer. Gene expression profiling of metastatic carcinomas, therefore, identified molecular pathways and functional gene families that are deregulated during malignant progression in canine mammary tumors.
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PMID:The metastatic cascade is reflected in the transcriptome of metastatic canine mammary carcinomas. 2111 1


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