Expression of high-mobility-group-protein HMGI-C mRNA in the peripheral blood is an independent poor prognostic indicator for survival in metastatic breast cancer

Langelotz, Corinna; Schmid, Peter; Jakob, Christian; Heider, Ulrike; Wernecke, Klaus‐D.; Possinger, K.; Sezer, Orhan

doi:10.1038/sj.bjc.6600935

Cited by 68 publications

(50 citation statements)

References 23 publications

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“…Consistently, elevated HMGA2 expression was found in many, but not all, BRCA1-deficient mouse mammary tumors and human breast cancer cells, including HCC1937 (BRCA1-deficient cell) (Fig. 6, A and B) (12). It is likely that other regulatory mechanisms remain effective in some tumors.…”

Section: Discussionmentioning

confidence: 49%

“…The HMGA2 architectural protein is critical for a variety of cellular processes, including gene transcription, induction of neoplastic transformation, and promotion of metastatic progression (10,11). Importantly, HMGA2 overexpression in tumors is associated with poor prognosis and metastasis in breast cancer patients (12). Although it is known that transcriptional repression of HMGA2 may prevent mammary tumorigenesis, the mechanisms governing repression remain elusive.…”

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confidence: 99%

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Derepression of HMGA2 via Removal of ZBRK1/BRCA1/CtIP Complex Enhances Mammary Tumorigenesis

Ahmed

Tsai

Lee

2010

Journal of Biological Chemistry

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The high mobility group AT-hook 2 (HMGA2), a DNA architectural protein, is highly regulated during development and plays an important role in tumorigenesis. Indeed, HMGA2 was overexpressed in many different kinds of tumors. However, the mechanisms regulating HMGA2 expression remain elusive. Using microarray analysis, we found that HMGA2, along with a dozen of other genes, was co-repressed by ZBRK1, BRCA1, and CtIP. BRCA1 exerts its transcriptional repression activity through interaction with the transcriptional repressor ZBRK1 in the central domain, and with CtIP in the C-terminal BRCT domain. Here, we show that ZBRK1, BRCA1, and CtIP form a repression complex that coordinately regulates HMGA2 expression via a ZBRK1 recognition site in the HMGA2 promoter. Depletion of any of the proteins in this complex via adenoviral RNA interference in MCF10A mammary epithelial cells activates HMGA2 expression, resulting in increased colony formation in soft agar. Similarly, depletion of ZBRK1, or ectopic overexpression of HMGA2, in MCF10A cells induces abnormal acinar size with increased cell number and inhibits normal acinar formation. Consistently, many BRCA1-deficient mouse breast tumors express higher levels of HMGA2 than BRCA1-proficient tumors. These results suggest that activation of HMGA2 gene expression through derepression of the ZBRK1/ BRCA1/CtIP complex is a significant step in accelerating breast tumorigenesis.The HMGA family consists of four proteins: HMGA1a, HMGA1b, HMGA1c, and HMGA2.2 HMGA1a, -b, and -c are all encoded by the same gene but vary in length due to alternative splicing (1-3), whereas HMGA2 is encoded by a distinctive gene (4). The common structural motifs in this group include an acidic C terminus and three DNA binding domains called A-T hooks, because they bind short (4 Ϯ 6 bp) AT-rich sequences in the minor groove (5-8). HMGA proteins regulate the expression of many genes through architectural remodeling of the chromatin structure and the formation of multiprotein complexes on promoter/enhancer regions. In accordance with their many roles in transcriptional regulation, aberrant expression of HMGA proteins has been observed in a large number of human cancers (reviewed by Farnet et al. (9)). The HMGA2 architectural protein is critical for a variety of cellular processes, including gene transcription, induction of neoplastic transformation, and promotion of metastatic progression (10, 11). Importantly, HMGA2 overexpression in tumors is associated with poor prognosis and metastasis in breast cancer patients (12). Although it is known that transcriptional repression of HMGA2 may prevent mammary tumorigenesis, the mechanisms governing repression remain elusive.The potential role of BRCA1 in transcriptional regulation has been revealed by discovering its ability to bind many important transcription factors, including p53, c-Myc, and STAT1 (13-15). Expression of several target proteins, including p21 WAF1 , cyclin B1, and EGR1, is activated or repressed by the presence of BRCA1. BRCA1 lacks DNA sequence...

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Section: Discussionmentioning

confidence: 49%

mentioning

confidence: 99%

Derepression of HMGA2 via Removal of ZBRK1/BRCA1/CtIP Complex Enhances Mammary Tumorigenesis

Ahmed

Tsai

Lee

2010

Journal of Biological Chemistry

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“…Results from a number of in vitro and transgenic models and human cancer studies have established a direct correlation between a high expression level of HMGA family members and increasing degrees of neoplastic transformation (3,7,9). For example, HMGA2 interacts with pRB to displace HDAC1, resulting in the enhanced activity of E2F1 (37).…”

Section: Discussionmentioning

confidence: 99%

“…Third, the expression of HMGA2 in oral squamous cell carcinoma is associated with increased disease recurrence and metastasis, along with a reduced survival rate manifested by a facilitated epithelial-mesenchymal transition (8). Moreover, HMGA2 expression is associated with the poor prognosis and metastasis in patients with breast cancer (9).…”

Section: Introductionmentioning

confidence: 99%

SUMOylation of HMGA2: selective destabilization of promyelocytic leukemia protein via proteasome

Cao

Clavijo

et al. 2008

Molecular Cancer Therapeutics

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The HMGA2 architectural protein functions in a variety of cellular processes, such as cell growth, transcription regulation, neoplastic transformation, and progression. Up-regulation of HMGA2 protein is observed in many tumors and is associated with advanced cancers with poor prognoses. Although the expression and biochemical properties of HMGA2 protein are regulated by microRNA and phosphorylation, it is unknown whether HMGA2 activity can also be regulated by SUMOylation, and that is what is investigated in this report. We identified HMGA2 as a SUMOylation target and showed that the expression of wild-type HMGA2, but not SUMOylation-defective HMGA2(2K/R), selectively lowered the steady-state level of PML protein. Consequently, the HMGA2-elicited PML down-regulation rendered a reduction in the average number of PML nuclear bodies per cell and the volume of PML assembled per PML nuclear body. Using small interfering RNA to suppress endogenous ubiquitin expression and proteasome inhibitor to repress ubiquitin-mediated protein degradation, we showed that HMGA2 confers PML down-regulation through ubiquitin-proteasomedependent protein degradation. Importantly, arsenic trioxide treatment stimulated HMGA2 SUMOylation, leading to the formation of HMGA2 nuclear foci surrounding PML nuclear bodies and the stimulation of PML degradation.Collectively, our results unveil a previously unrecognized effect by HMGA2 on the modulation of PML protein level, providing a novel mechanism underlying HMGA2 function and underscoring the molecular basis for oncogenic progression by HMGA2. [Mol Cancer Ther 2008;7(4):923-34]

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“…HMGA1a has already been shown to regulate negatively the expression of BRCA1, which may account for reduced BRCA1 expression in sporadic breast cancer (Baldassarre et al, 2003). In addition, increased levels of HMGA1 have been associated with a poor prognosis (Langelotz et al, 2003) and an increased tumor grade (Flohr et al, 2003) in human breast cancer.…”

Section: Introductionmentioning

confidence: 99%

Human KIT ligand promoter is positively regulated by HMGA1 in breast and ovarian cancer cells

et al. 2004

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KIT ligand (KL) and its receptor, c-kit, are coexpressed in many types of cancer cells and have been implicated in tumor growth and angiogenesis. While Sertoli cell-specific regulation of the KL promoter has been well characterized, regulation in cancer cells remains to be elucidated. We recently reported microarray results demonstrating that increased high-mobility group (HMG) A1a protein expression correlates with increased KL transcription in MCF-7 human breast cancer cells. Sequence analysis indicates a potential for multiple HMGA1 binding sites within the human KL promoter. In order to better define the underlying molecular mechanisms that HMGA1 uses to facilitate malignant transformation of cancer cells, we have used a variety of methods to determine whether HMGA1a directly regulates the human KL promoter in breast and ovarian cancer cells. Our results indicate that: (i) KL promoter activity is significantly higher in MCF-7 cells overexpressing HMGA1a; (ii) HMGA1a protein binds to AT-rich regions of the KL promoter DNA both in vitro and in vivo; (iii) mutation of the AT-rich regions inhibits HMGA1a binding in vitro; and (iv) HMGA1a-specific inhibition significantly decreases transcription of KL in OCC1 human ovarian cancer cells. In addition, MCF-7 cells with transgenic HMGA1 overexpression stained positive for the KL protein by immunocytochemistry and immunohistochemistry, and were growth-inhibited by KL neutralization. The cumulative evidence indicates that HMGA1 positively regulates the human KL promoter in breast and ovarian cancer cells and implicates serum KL as a diagnostic marker for HMGA1-positive carcinomas.

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Expression of high-mobility-group-protein HMGI-C mRNA in the peripheral blood is an independent poor prognostic indicator for survival in metastatic breast cancer

Cited by 68 publications

References 23 publications

Derepression of HMGA2 via Removal of ZBRK1/BRCA1/CtIP Complex Enhances Mammary Tumorigenesis

Derepression of HMGA2 via Removal of ZBRK1/BRCA1/CtIP Complex Enhances Mammary Tumorigenesis

SUMOylation of HMGA2: selective destabilization of promyelocytic leukemia protein via proteasome

Human KIT ligand promoter is positively regulated by HMGA1 in breast and ovarian cancer cells

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