Expression of the NF-κB-responsive gene BTG2 is aberrantly regulated in breast cancer

Kawakubo, Hirofumi; Carey, Jennifer; Brachtel, Elena F.; Gupta, Vandana; Green, Jeffrey E.; Walden, Paul D.; Maheswaran, Shyamala

doi:10.1038/sj.onc.1208008

Cited by 68 publications

(92 citation statements)

References 42 publications

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“…Identification of BTG2 as a transcriptional target of p53 (Cortes et al, 2000), and as a key mediator of p53-dependent cellular transformation of mouse and human fibroblasts transduced with oncogenic Ras (Boiko et al, 2006), suggests that it has an important role in inhibiting tumorigenesis. This is consistent with the repression of BTG2 expression in several human tumors including the breast, thymus, prostate and kidney (Lim et al, 1995;Ficazzola et al, 2001;Kawakubo et al, 2004Kawakubo et al, , 2006Struckmann et al, 2004). Moreover, expression of BTG2 in a mouse model for medulloblastoma suppressed the formation of tumors (Farioli-Vecchioli et al, 2007).…”

Section: Introductionsupporting

confidence: 83%

“…We had previously shown that loss of BTG2 protein in breast cancer is associated with higher tumor grade and size and overexpression of the cyclin D1 protein (Kawakubo et al, 2004(Kawakubo et al, , 2006. Analysis of several Oncomine microarray data sets corroborated these findings and revealed a strong correlation between decreased BTG2 expression in breast cancer and characteristics of tumor progression.…”

Section: Discussionmentioning

confidence: 55%

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Breast tumor progression induced by loss of BTG2 expression is inhibited by targeted therapy with the ErbB/HER inhibitor lapatinib

et al. 2011

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The B-cell translocation gene-2 (BTG2), a p53-inducible gene, is suppressed in mammary epithelial cells during gestation and lactation. In human breast cancer, decreased BTG2 expression correlates with high tumor grade and size, p53 status, blood and lymph vessel invasion, local and metastatic recurrence and decrease in overall survival, suggesting that suppression of BTG2 has a critical role in disease progression. To analyze the role of BTG2 in breast cancer progression, BTG2 expression was knocked down in mammary epithelial cells. Suppression of BTG2 enhances the motility of cells in vitro and tumor growth and metastasis in vivo. The effects of BTG2 knockdown are mediated through stabilization of the human epidermal growth factor receptor (HER) ligands neuregulin and epiregulin and activation of the HER2 and HER3 receptors, leading to elevated AKT phosphorylation. Suppression of HER activation using the tyrosine kinase inhibitor lapatinib abrogates the effects of BTG2 knockdown, including the increased cell migration observed in vitro and the enhancement of tumorigenesis and metastasis in vivo. These results link BTG2-dependent effects on tumor progression to ErbB receptor signaling, and raise the possibility that targeted inhibition of this pathway may be relevant in the treatment of breast cancers that have reduced BTG2 expression.

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Section: Introductionsupporting

confidence: 83%

Section: Discussionmentioning

confidence: 55%

Breast tumor progression induced by loss of BTG2 expression is inhibited by targeted therapy with the ErbB/HER inhibitor lapatinib

et al. 2011

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“…A loss of nuclear BTG2 expression is observed in ERα positive human breast tumors (Kawakubo et al, 2006), and an inverse correlation between breast tumor size and BTG2 expression has also been demonstrated (Kawakubo et al, 2006). BTG2 mRNA levels have been shown to be decreased by E2 and progestins in MCF-7 and T-47D breast cancer cells, respectively (Kawakubo et al, 2004). To the best of our knowledge this is however the first report on FGF-mediated repression of Btg2.…”

Section: Discussionmentioning

confidence: 85%

Identification of fibroblast growth factor-8b target genes associated with early and late cell cycle events in breast cancer cells

Nilsson

Brokken

Narvi

et al. 2012

Molecular and Cellular Endocrinology

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(2012). Identification of fibroblast growth factor-8b target genes associated with early and late cell cycle events in breast cancer cells. Molecular and Cellular Endocrinology, 358(1), 104-115. DOI: 10.1016/j.mce.2012.03.009 General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights.• Users may download and print one copy of any publication from the public portal for the purpose of private study or research.• You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal

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“…Moreover, BTG2 /TIS21 expression is very low or undetectable in human breast cancer cell lines, compared with non-tumorigenic mammary epithelial cell, however, it is stimulated in breast cancer cells by the activation of nuclear factor kappa B. In rat mammary glands, the BTG2 /TIS21 expression in epithelial cells is decreased during pregnancy and lactation, but recovered during involution (Kawakubo et al 2004), suggesting that estrogen and progestin may downregulate BTG2 /TIS21 in the mammary gland during pregnancy. These data indicate that the deregulation of BTG2 /TIS21 early at the tumorigenic process may also be an important step in the development of mammary tumors.…”

Section: Potential Function Referencementioning

confidence: 98%

“…Suppression of BTG2 /TIS21 mRNA in the mammary gland during pregnancy and lactation and treatment of the cells with estrogen and progestin stimulate cyclin D1 expression. Furthermore, ectopic expression of BTG2 /TIS21 inhibits breast cancer cell growth by arresting the cells at G1 phase, and the effect is reversed by cyclin D1 (Kawakubo et al 2004). Therefore, TIS21 /BTG2//PC3 induces the cell cycle arrest through at least two pathways: cyclin D1 and cyclin E. The latter becomes prominent when the function of pRB and possibly other cell cycle regulators such as p53 are impaired.…”

Section: Tis21mentioning

confidence: 99%

TIS21 /BTG2/PC3 as a link between ageing and cancer: cell cycle regulator and endogenous cell death molecule

Lim

2006

J Cancer Res Clin Oncol

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TIS21/BTG2/PC3 , orthologs of mouse, human and rat, respectively, is initially identified as one of the early growth response genes and induced by various stimulations. TIS21 belongs to antiproliferative (APRO) gene family containing the BTG-Box A (Y 50 -N 71 ) and BTG-Box B (L 97 -E 115 ), which are highly conserved among various species. On the other hand, it has lately been found that the expression of TIS21 is constitutive and high in thymus, lung alveolar epithelium, proximal tubule of kidney and basal cell layer of prostate acini. Potential roles of TIS21 have been suggested as transcriptional co-regulator, differentiation and antiapoptotic factor in neurogenesis, key mediator of the stagespecific expansion of thymocyte and negative regulator of hematopoietic progenitor expansion, and tumor suppressor gene in both mouse and human. In addition, as pan-cell cycle regulator TIS21 induces G1/S arrest by pRB dependently and pRB independently and G2/M arrest and cell death in the p53 null tumor cells, and regulates the development of vertebrate patterning in mouse, paraxial mesoderm development in zebrafish, and notochord development in Xenopus. It has been known that the expression of TIS21 depends on the induction of wt p53 when cells are damaged, however, it can also be upregulated p53 independently by the activation of PKC-d pathway in tumor cells. The characteristic roles of TIS21 are discussed in the present review: (1) TIS21 inhibits early phase of carcinogenesis in its high expressers such as kidney, prostate, breast and thymus: Loss of constitutive and high expression of TIS21 was observed in the precancerous lesions as well as tumor tissues. As an endogenous cell death molecule, TIS21 may be involved in translocation of Pin-1 to cytoplasm. Pin-1 subsequently interacts with Serine 147 residue in TIS21 protein, resulting in mitochondrial depolarization. (2) TIS21 regulates transition of cell cycle at G1/S and G2/M phases in cancer cells with inactive pRB and/or p53, as well as in normal cells by regulating pRB/p16INK4a pathway. The latter has already been well elucidated; TIS21 inhibits the expression of cyclin D1, thus resulting in the arrest of cells at G1/S phase by pRB and p53 dependent manner. On the other hand, TIS21 inhibits degradations of cyclin A and cyclin B1 at G2/M phase, and directly binds to Cdc2, resulting in the failure of mitotic exit and then increasing the tumor cell death, when stimulated by high concentration of EGF. Therefore, TIS21 can be suggested as a pan-cell cycle modulator. (3) TIS21 regulates embryo development by activating BMP signal through interaction with Smad 1 and Smad 8, thereby regulating vertebral patterning in mice. It is also involved in notochord development in Xenopus and paraxial mesoderm development in zebrafish. Based on the previous report that the expression of TIS21 is involved in the induction of senescence after chemotherapy of cancer cells, which can be a mechanism to resist carcinogenesis, TIS21 /BTG2/ PC3 , the endogenous cell death mol...

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Expression of the NF-κB-responsive gene BTG2 is aberrantly regulated in breast cancer

Cited by 68 publications

References 42 publications

Breast tumor progression induced by loss of BTG2 expression is inhibited by targeted therapy with the ErbB/HER inhibitor lapatinib

Breast tumor progression induced by loss of BTG2 expression is inhibited by targeted therapy with the ErbB/HER inhibitor lapatinib

Identification of fibroblast growth factor-8b target genes associated with early and late cell cycle events in breast cancer cells

TIS21 /BTG2/PC3 as a link between ageing and cancer: cell cycle regulator and endogenous cell death molecule

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