Gene Expression Analysis of Immune-Mediated Arrest of Tumorigenesis in a Transgenic Mouse Model of HER-2/neu-Positive Basal-Like Mammary Carcinoma

Astolfi, Annalisa; Landuzzi, Lorena; Nicoletti, Giordano; Giovanni, Carla De; Croci, Stefania; Palladini, Arianna; Ferrini, Silvano; Iezzi, Manuela; Musiani, Piero; Cavallo, Federica; Forni, Guido; Nanni, Patrizia; Lollini, Pier‐Luigi

doi:10.1016/s0002-9440(10)62339-5

Cited by 44 publications

(35 citation statements)

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“…While their involvement in breast cancer has never been described, by exploiting data on the expression of miRNAs in human breast cancers [70,73], the over-expression of miR-135b, but not miR-135a, appeared to be associated with poor prognosis. In addition, miR-135b overexpression in basal-like and estrogen-negative human tumor shown by this meta analysis fits in well with the notion that mammary tumors of our HER-2 trasngenic mice are similar to basal-like and estrogen-negative human mammary carcinomas [76]. Down-modulation of miR-135b in cancer cells from HER-2 transgenic mice revealed its major role in anchorage-independent growth and lung metastasis formation.…”

Section: Discovery Of Novel Oncoantigens -Preneoplastic Lesions Diffsupporting

confidence: 87%

Preclinical vaccines against mammary carcinoma

Lollini

Cavallo

Giovanni

et al. 2013

Expert Review of Vaccines

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SummaryVaccines against human breast cancer are an unfulfilled promise.Despite decades of promising preclinical and clinical research, no vaccine is currently available for breast cancer patients. Preclinical research has much to do with this failure, because early mouse models of mammary carcinoma did not mirror the molecular, cellular, antigenic and immunological features of human breast cancer. The advent of HER-2 transgenic mice gave impulse to a new generation of cell and DNA vaccines against mammary carcinoma, that in turn led to the definition of significant antigenic (oncoantigens) and cellular (cancer-initiating cells, preneoplastic lesions, incipient metastases) targets.Future preclinical developments will include the discovery of novel oncoantigens in HER-2-negative mammary carcinoma and the targeting of activated HER-2 molecular variants. Translation to clinically effective vaccines will be fostered not only by new preclinical model systems, but also by the possibility to conduct veterinary vaccination trials in companion animals. Keywords Preclinical models of mammary carcinoma for tumor immunologyResearch on mammary carcinoma is inextricably interwoven with the history of preclinical models, starting with the development in the 1920s of the C3H mouse strain, selected for a high incidence of mammary tumors. It is a history that illustrates very well some critical issues of preclinical models in general [1]. On the one side, the C3H model of mammary carcinoma, caused by the mouse mammary tumor virus (MMTV), is no longer regarded as a reliable model for human breast cancer, which is not caused by viruses. On the other side, the discovery of MMTV and the analysis of its oncogenic activity were key steps in the development of molecular oncology, eventually leading to the discovery of various oncogenes.Today MMTV continues to contribute to mammary carcinoma preclinical models, because its (relative) tissue specificity was harnessed to drive the expression of oncogenes and other genes in the mammary gland, and many transgenic mice prone to mammary carcinoma in use today were designed using (non-coding) MMTV sequences [2]. Cell linesIn addition to the viral etiology, MMTV-infected mice have . These cell lines were thought to reproduce the low immunogenicity of human tumors, thus giving rise to more faithful preclinical models for vaccination studies. While it is true that cell lines like TS/A were poorly immunogenic, in retrospect they were not exempt from the "viral sin", because in many instances the immunodominant antigens were later shown by molecular studies to be related to endogenous retroviral sequences [4,5]. Genetically modified miceThe advent of genetically modified mice has revolutionized biomedical research, allowing the establishment of preclinical models of human diseases for which no equivalent spontaneous mouse pathology existed or was not a faithful model of human disease, as is the case of mammary carcinoma.Immunological studies focused on HER-2 transgenic mice, that offered for the fir...

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Section: Discovery Of Novel Oncoantigens -Preneoplastic Lesions Diffsupporting

confidence: 87%

Preclinical vaccines against mammary carcinoma

Lollini

Cavallo

Giovanni

et al. 2013

Expert Review of Vaccines

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“…These findings were not unexpected because Mena protein, as well as the other members of the Ena/VASP family, localize to the focal adhesions, lamellipodial protrusions, and filopodia tips, where they control highly dynamic processes requiring a strict regulation of the actin cytoskeleton changes, such as fibroblast protrusion and migration (3), intracellular bacterial motility (19), and axon and dendritic guidance (20). A recent study on the gene expression signature in HER-2/neu-transgenic mice, a suitable model for mammary carcinogenesis, has shown Mena (ENAH) overexpression during HER-2-induced breast cancer progression (21), suggesting that signaling pathways related to different epidermal growth factor receptor family members may also modulate hMena. In line with these data, our results show a significant direct relationship between hMena and HER-2 overexpression.…”

Section: Discussionmentioning

confidence: 99%

The Cytoskeleton Regulatory Protein hMena (ENAH) Is Overexpressed in Human Benign Breast Lesions with High Risk of Transformation and Human Epidermal Growth Factor Receptor-2–Positive/Hormonal Receptor–Negative Tumors

Modugno¹,

Mottolese²,

Benedetto³

et al. 2006

Clinical Cancer Research

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Purpose: hMena (ENAH), a cytoskeleton regulatory protein involved in the regulation of cell motility and adhesion, is overexpressed in breast cancer. The aim of this study was to define at what stage of breast carcinogenesis hMena is overexpressed and to correlate hMena overexpression with established prognostic factors in breast cancer, focusing on human epidermal growth factor receptor-2 (HER-2). Experimental Design: hMena expression was assessed immunohistochemically in a prospective cohort of cases (n = 360) encompassing a highly representative spectrum of benign breast diseases associated with different risk of transformation, in situ, invasive, and metastatic tumors. Correlations with conventional pathologic and prognostic variables, such as proliferation index, hormonal receptor status, and HER-2 overexpression, were also evaluated. In vitro experiments were done to study the effect of neuregulin-1and Herceptin treatments on hMena expression. Results: hMena protein is undetectable in normal breast and is weakly expressed in a small percentage of low-risk benign diseases (9%), but displays a progressive and significant increase of positivity in benign lesions at higher risk of transformation (slightly increased risk 43%; moderate increased risk 67%), in in situ (72%), invasive (93%), and metastatic breast cancer (91%).A significant direct correlation with tumor size (P = 0.04), proliferation index (P < 0.0001), and HER-2 overexpression (P < 0.0001) and an inverse relationship with estrogen (P = 0.036) and progesterone receptors (P = 0.001) are found in invasive carcinomas. In vitro experiments show that neuregulin-1up-regulates, whereas Herceptin down-regulates, hMena expression. Conclusions: Our data provide new insights into the relevance of actin-binding proteins in human breast carcinogenesis and indicate hMena overexpression as a surrogate indicator in breast disease management. Management of breast cancer, and other malignancies, islikely to benefit from the identification of early markers of transformation. In this context, major efforts are ongoing in the areas of genomic and proteomic profiling aimed at identifying genetic or biochemical markers related to proliferative lesions heralding the development of breast cancer. In view of the increasing evidence that the host immune response contributes to the editing of the tumor phenotype (1), we have recently isolated, by serologic analysis of cDNA expression libraries (SEREX), hMena (ENAH) protein, the human orthologue of murine Mena, which is overexpressed in over 70% of primary breast cancers (2). Mena belongs to the Ena/VASP protein family, which, by controlling the geometry of the actin filament network (3, 4), represents key regulator molecules of cell movement and shape in a large variety of cell types and organisms (5). It has been suggested that Ena/VASP proteins are members of the adherens junction structures and are required for the actin dynamics necessary to seal membranes into epithelial sheets (6), a process frequently deregula...

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“…Several studies have reported the mRNA expression profiles of Her2-positive tumors from microarray analysis [43,44]. However, validation of the long lists of biomarker candidates identified using either proteomic or genomic approaches is challenging.…”

Section: Identification Of Novel Biomarkersmentioning

confidence: 99%

Proteomic characterization of Her2/neu‐overexpressing breast cancer cells

Chen¹,

Pimienta²,

Gu³

et al. 2011

Proteomics Clinical Apps

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The receptor tyrosine kinase HER2 is an oncogene amplified in invasive breast cancer and its overexpression in mammary epithelial cell lines is a strong determinant of a tumorigenic phenotype. Accordingly, HER2-overexpressing mammary tumors are commonly indicative of a poor prognosis in patients. Several quantitative proteomic studies have employed two-dimensional gel electrophoresis in combination with tandem mass spectrometry, which provides only limited information about the molecular mechanisms underlying HER2/neu signaling. In the present study, we used a SILAC-based approach to compare the proteomic profile of normal breast epithelial cells with that of Her2/neu-overexpressing mammary epithelial cells, isolated from primary mammary tumors arising in MMTV-Her2/neu transgenic mice. We identified 23 proteins with relevant annotated functions in breast cancer, showing a substantial differential expression. This included overexpression of creatine kinase, retinol-binding protein 1, thymosin beta 4 and tumor protein D52, which correlated with the tumorigenic phenotype of Her2-overexpressing cells. The differential expression pattern of two genes, gelsolin and retinol binding protein 1, was further validated in normal and tumor tissues. Finally, an in silico analysis of published cancer microarray datasets revealed a 23-gene signature which can be used to predict the probability of metastasis-free survival in breast cancer patients.

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Gene Expression Analysis of Immune-Mediated Arrest of Tumorigenesis in a Transgenic Mouse Model of HER-2/neu-Positive Basal-Like Mammary Carcinoma

Cited by 44 publications

References 43 publications

Preclinical vaccines against mammary carcinoma

Preclinical vaccines against mammary carcinoma

The Cytoskeleton Regulatory Protein hMena (ENAH) Is Overexpressed in Human Benign Breast Lesions with High Risk of Transformation and Human Epidermal Growth Factor Receptor-2–Positive/Hormonal Receptor–Negative Tumors

Proteomic characterization of Her2/neu‐overexpressing breast cancer cells

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