Characterization and chromosomal instability of novel derived cell lines from a wt-erbB-2 transgenic mouse model

Jeruss, Jacqueline S.; Liu, Na Xin; Chung, Yongji; Magrane, Gregg; Waldman, Frederic M.; Edgerton, Susan M.; Yang, Xiaohe; Thor, Ann D.

doi:10.1093/carcin/bgg001

Cited by 12 publications

(16 citation statements)

References 31 publications

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“…common but trisomy chromosome 5 was not detected (10). In the context of these studies, our current results suggest that cytogenetic changes in tumors from parous mice, not only occur at a higher frequency, but also indicate a pattern that is inconsistent with that reported in previous studies.…”

contrasting

confidence: 63%

“…Trisomy 5 and loss of X chromosome appear to be associated with enhanced overexpression and activation of erbB-2. Notably, although the chromosome 4 deletion was a common lesion detected in previous studies (9,10), this deletion is not the most common change (2 in 5 cell lines) evident in the current study. Nevertheless, repeated detection of chromosome 4 deletion in various studies underscores its significance in erbB-2-mediated genomic instability.…”

contrasting

confidence: 58%

“…The most common chromosomal abnormalities were loss of mouse chromosome 4 and gain of chromosome 10 (10). We also revealed that tumors and tumor cell lines derived from MMTV-erbB-2 mice treated with E2 or soy appeared to have more cytogenetic lesions (10). These results suggest that the chromosomal imbalance in the erbB-2-associated cytogenetic changes are affected by erbB-2 signaling activity (mutant or activated erbB-2 induces stronger carcinogenic activity) and hormonal conditions.…”

Section: Introductionmentioning

confidence: 61%

“…Tumors were aseptically removed from the animals and immediately processed during the tumor harvest (10,13). Tumor tissues were minced with scissors and then washed with PBS.…”

Section: Methodsmentioning

confidence: 99%

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Trisomy chromosome 5 is a recurrent cytogenetic lesion in mammary tumors from parous MMTV-erbB-2 transgenic mice

Kim

Lee

et al. 2011

Oncology Letters

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Abstract. erbB-2 is amplified or overexpressed in approximately 30% of human breast cancers, and has been associated with poor prognosis and therapeutic resistance. Previous studies have suggested that erbB-2 overexpression in transgenic mice induces genomic instability; however, the patterns of genetic lesions vary with individual model systems. The development of mammary tumors in multiparous murine mammary tumor virus (MMTV)-erbB-2 transgenic mice is accelerated due to hormonal interactions which induce the overexpression of MMTV-mediated erbB-2. However, whether or not accelerated tumor development is associated with modified cytogenetic patterns remains to be determined. In this study, chromosomal changes were characterized in mammary tumor cells derived from multiparous MMTVerbB-2 transgenic mice, and compared with tumor cells derived from control virgin mice. Immunohistochemistry and Western blotting were used to detect erbB-2 overexpression in mammary tissues. Each of the five tumors from the multiparous MMTV-erbB-2 transgenic mice was found to exhibit a marked chromosomal imbalance, compared with only one tumor with aberrant chromosomes among the five tumors from the control virgin mice. In particular, trisomy 5 and loss of the X chromosome were recurrent cytogenetic lesions in tumors from the parous mice, which is a novel pattern compared with previous studies. The elevated number of genetic lesions in tumors from parous mice, which were characterized by enhanced erbB-2 overexpression and increased receptor tyrosine kinase activation in the mammary glands, suggest a causal role for erbB-2 in the genomic instability present in these tumors. These data advance our understanding of erbB-2-mediated pathogenesis and underscore the role of cytogenetic alteration in this process. IntroductionerbB-2 (HER2, Neu) is a receptor tyrosine kinase of the EGFR family (1,2). erbB-2 is amplified/overexpressed in approximately 30% of primary human breast cancers, and has been associated with poor prognosis and therapeutic resistance (3,4). erbB-2 overexpression and/or activation induces the subsequent activation of a plethora of signaling pathways, including those that are mediated by MAP kinase, PI3 kinase, and the STAT family of transcription factors (5,6). These activated signaling pathways ultimately increase cell proliferation, reduce apoptosis, and induce cell transformation (7). erbB-2-associated carcinogenesis has been extensively studied. However, since erbB-2 activation elicits signaling in diversified downstream pathways, the precise mechanisms involved in erbB-2-mediated carcinogenesis remain unclear.erbB-2 transgenic mouse models were utilized in numerous studies in order to understand erbB-2-mediated carcinogenesis (8). The association of erbB-2 overexpression with genomic instability is of marked interest. Montagna et al reported that tumor cell lines from transgenic mice overexpressing constitutively activated mutant erbB-2/Neu exhibited recurrent deletions of chromosome 4, amplification of chromosome 11,...

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contrasting

confidence: 63%

contrasting

confidence: 58%

Section: Introductionmentioning

confidence: 61%

“…Tumors were aseptically removed from the animals and immediately processed during the tumor harvest (10,13). Tumor tissues were minced with scissors and then washed with PBS.…”

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Trisomy chromosome 5 is a recurrent cytogenetic lesion in mammary tumors from parous MMTV-erbB-2 transgenic mice

Kim

Lee

et al. 2011

Oncology Letters

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“…Key features of HER2 deregulation are chromosome instability, disruption of mitotic checkpoints, deregulation of the cell death programmes, and enhanced cell cycle progression (12,13). Recent research has highlighted the FoxM1 transcription factor, a member of the Forkhead box family, as a ubiquitously expressed key transcriptional regulator of the cell cycle (14,15).…”

Section: Introductionmentioning

confidence: 99%

FoxM1 is a downstream target and marker of HER2 overexpression in breast cancer

Francis

Myatt²,

Krol³

et al. 2009

Int J Oncol

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Abstract. The tyrosine kinase receptor, HER2 is a crucial prognostic marker and therapeutic target for breast cancer; however, the downstream targets and biological effectors of HER2 remain unclear. We investigated the relationship between HER2 and the transcription factor FoxM1 in breast cancer. HER2 and FoxM1 expression levels were compared in breast carcinoma cell lines, paraffin-embedded breast cancer patient samples and at the mRNA level in purified breast epithelial cells. To further examine the relationship between HER2 and FoxM1 expression, we either overexpressed or siRNA-mediated depleted endogenous HER2 in breast cancer cell lines. Additionally, a mammary epithelium-targeted HER2 (neu) transgenic mouse model was also used to assess the effect of HER2 on FoxM1 levels. Furthermore, the effect of the HER2-tyrosine kinase inhibitor lapatinib on FoxM1 in HER2 positive breast cancer cells was investigated. HER2 protein levels directly correlated with FoxM1 expression in both breast carcinoma cell lines and paraffin-embedded breast cancer patient samples. Moreover, in purified breast epithelial cells, overexpression of HER2 was associated with high levels of FoxM1 mRNA, suggesting that the upregulation of FoxM1 expression is at least partially mediated transcriptionally. Furthermore, overexpression or ablation of endogenous HER2 resulted in parallel changes in FoxM1 expression. Critically, mammary epithelium-targeted HER2 mouse tumours also resulted in increased FoxM1 expression, suggesting that HER2 directed FoxM1 expression occurs in vivo and may be a critical downstream effector of HER2-targeting therapies. Indeed, treatment of breast cancer cells with lapatinib reduced FoxM1 expression at protein, mRNA and gene promoter levels. Moreover, analysis of normal and breast cancer patient samples revealed that elevated FoxM1 expression at protein and mRNA levels correlated with breast cancer development, but not significantly with cancer progression and survival. Our results indicate that the HER2 receptor regulates the expression of the FoxM1 transcription factor, which has a role in breast cancer development.

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Dysfunctional telomeres promote genomic instability and metastasis in the absence of telomerase activity in oncogene induced mammary cancer

Bojović

Crowe

2011

Molecular Carcinogenesis

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Telomerase is a ribonucleoprotein that maintains the ends of chromosomes (telomeres). In normal cells lacking telomerase activity, telomeres shorten with each cell division because of the inability to completely synthesize the lagging strand. Critically shortened telomeres elicit DNA damage responses and limit cellular division and lifespan, providing an important tumor suppressor function. Most human cancer cells express telomerase which contributes significantly to the tumor phenotype. In human breast cancer, telomerase expression is predictive of clinical outcomes such as lymph node metastasis and survival. In mouse models of mammary cancer, telomerase expression is also upregulated. Telomerase overexpression resulted in spontaneous mammary tumor development in aged female mice. Increased mammary cancer also was observed when telomerase deficient mice were crossed with p53 null mutant animals. However, the effects of telomerase and telomere length on oncogene driven mammary cancer have not been completely characterized. To address these issues we characterized neu proto-oncogene driven mammary tumor formation in G1 Terc-/- (telomerase deficient with long telomeres), G3 Terc-/- (telomerase deficient with short telomeres), and Terc+/+ mice. Telomerase deficiency reduced the number of mammary tumors and increased tumor latency regardless of telomere length. Decreased tumor formation correlated with increased apoptosis in Terc deficient tumors. Short telomeres dramatically increased lung metastasis which correlated with increased genomic instability, and specific alterations in DNA copy number and gene expression. We concluded that short telomeres promote metastasis in the absence of telomerase activity in neu oncogene driven mammary tumors.

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Characterization and chromosomal instability of novel derived cell lines from a wt-erbB-2 transgenic mouse model

Cited by 12 publications

References 31 publications

Trisomy chromosome 5 is a recurrent cytogenetic lesion in mammary tumors from parous MMTV-erbB-2 transgenic mice

Trisomy chromosome 5 is a recurrent cytogenetic lesion in mammary tumors from parous MMTV-erbB-2 transgenic mice

FoxM1 is a downstream target and marker of HER2 overexpression in breast cancer

Dysfunctional telomeres promote genomic instability and metastasis in the absence of telomerase activity in oncogene induced mammary cancer

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