Human Growth Hormone-regulated HOXA1 Is a Human Mammary Epithelial Oncogene

Zhang, Xin; Zhu, Tao; Yong, Chen; Mertani, Hichem C.; Lee, Kok-Onn; Lobie, Peter E.

doi:10.1074/jbc.m212050200

Cited by 146 publications

(168 citation statements)

References 59 publications

(68 reference statements)

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“…To determine whether BCL-2 mediated ARTN-stimulated oncogenicity and antiestrogen resistance, we examined the anchorage-independent growth of MCF7-Vec and MCF7-ARTN cells in the presence of the BCL-2 inhibitor YC137 alone or in combination with tamoxifen or fulvestrant. As shown in Figure 5c, colony formation by MCF7-Vec cells was dramatically reduced by YC137, supportive of the reported function of BCL-2 in anchorage-independent growth (Zhang et al, 2003). YC137 also significantly abrogated the ARTN enhancement of colony formation in soft agar, suggestive that BCL-2 is required for ARTN-stimulated anchorage-independent growth.…”

Section: Artn Enhanced Er Transcriptional Activity and Functionsupporting

confidence: 78%

Artemin is estrogen regulated and mediates antiestrogen resistance in mammary carcinoma

et al. 2010

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We have previously identified an oncogenic role of artemin (ARTN), a member of glial cell derived neurotrophic factor family of ligands, in mammary carcinoma. We herein report that ARTN is an estrogen-inducible gene. Metaanalysis of gene expression data sets showed that ARTN expression is positively correlated to estrogen receptor (ER) status in human mammary carcinoma. Furthermore, in patients with ER-positive mammary carcinoma treated with tamoxifen, high ARTN expression is significantly correlated with decreased survival. Forced expression of ARTN in ER-positive human mammary carcinoma cells increased ER transcriptional activity, promoted estrogenindependent growth and produced resistance to tamoxifen and fulvestrant in vitro and to tamoxifen in xenograft models. ARTN-stimulated resistance to tamoxifen and fulvestrant is mediated by increased BCL-2 expression. Conversely, depletion of endogenous ARTN by smallinterfering RNA or functional antagonism of ARTN by antibody enhanced the efficacy of antiestrogens. Tamoxifen decreased ARTN expression in tamoxifen-sensitive mammary carcinoma cells whereas ARTN expression was increased in tamoxifen-resistant cells and not affected by tamoxifen treatment. Antibody inhibition of ARTN in tamoxifen-resistant cells improved tamoxifen sensitivity. Functional antagonism of ARTN therefore warrants consideration as an adjuvant therapy to enhance antiestrogen efficacy in ER-positive mammary carcinoma.

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Section: Artn Enhanced Er Transcriptional Activity and Functionsupporting

confidence: 78%

Artemin is estrogen regulated and mediates antiestrogen resistance in mammary carcinoma

et al. 2010

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“…It is unclear why the increased expressions of the 4 HOX genes are of advantage to metastasize; however, we speculate as follows. It is known that the expressions of HOXA1 and A2 are regulated by growth hormone and growth factors belonging to the fibroblast growth factor (FGF) family, respectively, 12,20 and that melanoma expresses growth hormone receptors and FGF receptors. [21][22][23] Therefore, the microenvironment including such hormones and growth factors may promote metastasis via changes of some HOX gene expressions.…”

Section: Discussionmentioning

confidence: 99%

“…Forced expression of HOXA1 in human breast cancer cells resulted in increased cell growth activity. 12 Our previous studies showed that human lung cancer A549 cells transfected with HOXD3 gene acquired more metastatic, invasive and motile phenotypes. 13,14 We also observed that the transduction of HOXD3-antisense expression vectors into human melanoma cells dramatically diminished their invasive and motile activities.…”

mentioning

confidence: 99%

Altered expressions of HOX genes in human cutaneous malignant melanoma

Maeda

Hamada

Takahashi

et al. 2004

Intl Journal of Cancer

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HOX genes act as master genes to control morphogenesis. In human, HOX genes form 4 clusters composing 9 to 11 HOX genes (39 genes in total) on different chromosomes. We hypothesized that aberrant expression of HOX genes was associated with development and subsequent progression of melanoma and that the 39 HOX gene expression pattern determined the sites where melanoma grew. The expression levels of 39 HOX genes in 15 human cutaneous melanoma specimens and 7 nevus pigmentosus specimens were quantified by a comprehensive analysis system based on the real-time RT-PCR method. We found that the expression levels of HOXA11, A13, B9, D12 and D13 in melanoma were higher than those in nevus pigmentosus and that the expression levels of HOXA11, B2 and C13 were significantly different between pT4 melanoma and pT1 to pT3 melanoma. It was most notable that the expression levels of HOXA1, A2, C4 and B13 in melanoma with distant metastasis were higher than those in melanoma without it. On the other hand, we found no relationship between HOX genes expression patterns and the growing sites of melanoma. These results indicated that the misexpressions of some specific HOX genes were implicated in melanoma genesis and metastasis but had no linkage with melanoma sites. © 2004 Wiley-Liss, Inc. Key words: melanoma; HOX; metastasis; nevus pigmentosusHox genes are one of the master regulators of morphogenesis and cell differentiation during embryogenesis of animals. 1 The genes contain a 180 bp DNA sequence (homeobox), which encodes a highly conserved 60 amino acid homeodomain. The HOX proteins function as transcription factors through their homeodomain, which is responsible for recognition and binding of sequence-specific DNA motifs. 2,3 In human genome, 39 HOX genes are clustered in a similar arrangement of 13 paralog groups in 4 different chromosomal regions, HOXA, B, C and D. 4 During embryonic morphogenesis, the HOX genes determine positional identity along the anterior-posterior and secondary axes in animals. Within each cluster, HOX genes located at the 3Ј extremity are activated first and in anterior embryonic domains, whereas 5Ј-located genes are transcribed subsequently and in more caudal areas, which is the property called colinearity rule. 5 HOX genes are also expressed in some normal adult organs in characteristic patterns, suggesting their possible role in the maintenance of tissuespecific architecture besides their roles in embryogenesis. 6 -9 Comparative analysis of HOX gene expression between cancerous tissues and normal tissues uncovered the dysregulated expression(s) of a particular HOX gene(s) in some kinds of carcinomas. For example, HOXB5 and B9 are expressed in normal kidney but not in renal cancer, whereas the expression of HOXC11 is observed in human renal cancer but not in normal kidney. 6 In human prostate cancer, overexpression of HOXC8 correlates with loss of differentiated phenotype. 10 Increased expressions of HOXC4, C5, C6 and C11 are likely to be involved in the development of human bladder transitiona...

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“…Forced expression of HOXA1 in human breast cancer cells results in increased cell growth activity (20). Loss of HOXC6 expression by transfection with siRNA induces apoptosis in human prostate cancer cell lines (21).…”

Section: Discussionmentioning

confidence: 99%

Disordered expression of HOX genes in human non-small cell lung cancer

Abe

Hamada²,

Takahashi³

et al. 2006

Oncol Rep

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We hypothesized that the disordered tissue architecture in cancer results from the steps that the cells execute the program designed during ontogeny in a spatiotemporally inappropriate manner. HOX genes are known as master regulators of embryonic morphogenesis, and encode transcription factors which regulate the transcription of the downstream genes to realize the program of body plan. In this study, we quantified the expression levels of 39 HOX genes in 41 human non-small cell lung cancer (non-SCLC) and non-cancerous lung tissues by a comprehensive analysis system based on the realtime RT-PCR method. We found that the expression levels of HOXA1, A5, A10 and C6 in squamous cell carcinoma tissues (and HOXA5 and A10 in adenocarcinoma tissues) were significantly higher than those in the non-cancerous tissues. Comparison of HOX gene expressions between adenocarcinoma and squamous cell carcinoma tissues showed higher expressions of HOXA1, D9, D10 and D11 in squamous cell carcinoma tissues than in adenocarcinoma tissues. Immunohistochemical analysis revealed that HOXA5 and A10 proteins were localized in the cytoplasm of tumor cells in both adenocarcinoma and squamous cell carcinoma tissues. These results suggest that the disordered patterns of HOX gene expressions were involved in not only the development of non-SCLC but also histological diversity such as adenocarcinoma and 4 squamous cell carcinoma.

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Human Growth Hormone-regulated HOXA1 Is a Human Mammary Epithelial Oncogene

Cited by 146 publications

References 59 publications

Artemin is estrogen regulated and mediates antiestrogen resistance in mammary carcinoma

Artemin is estrogen regulated and mediates antiestrogen resistance in mammary carcinoma

Altered expressions of HOX genes in human cutaneous malignant melanoma

Disordered expression of HOX genes in human non-small cell lung cancer

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