HOXB13 Homeodomain Protein Suppresses the Growth of Prostate Cancer Cells by the Negative Regulation of T-Cell Factor 4

Jung, Chang-Yeol; Kim, Ran-Sook; Lee, Sang-Jin; Wang, Chihuei; Jeng, Meei-Huey

doi:10.1158/0008-5472.can-03-2614

Cited by 95 publications

(103 citation statements)

References 36 publications

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“…Thus far, studies pertaining to the growth modulatory role of HOXB13 in human tumors have been limited to prostate and renal cell carcinoma cell lines. Interestingly, the results of these studies, in contrast to our findings, suggest that HOXB13 plays a tumor suppressor role in the kidney and prostate (14,18,19). These contradictory findings are not necessarily surprising, because it is well known that the activity of HOX proteins depends on the cell in which the protein is acting (20).…”

Section: Knockdown Of Endogenous Hoxb13 In Human Ovarian Cancer Cellcontrasting

confidence: 99%

HOXB13 promotes ovarian cancer progression

Miao

Wang

Provencher

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

105

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Deregulated expression of HOXB13 in a subset of estrogen receptor-positive breast cancer patients treated with tamoxifen monotherapy is associated with an aggressive clinical course and poor outcome. Because the ovary is another hormone-responsive organ, we investigated whether HOXB13 plays a role in ovarian cancer progression. We show that HOXB13 is expressed in multiple human ovarian cancer cell lines and tumors and that knockdown of endogenous HOXB13 by RNA interference in human ovarian cancer cell lines is associated with reduced cell proliferation. Ectopic expression of HOXB13 is capable of transforming p53 ؊/؊ mouse embryonic fibroblasts and promotes cell proliferation and anchorage-independent growth in mouse ovarian cancer cell lines that contain genetic alterations in p53, myc, and ras. In this genetically defined cell line model of ovarian cancer, we demonstrate that HOXB13 collaborates with activated ras to markedly promote tumor growth in vivo and that HOXB13 confers resistance to tamoxifen-mediated apoptosis. Taken together, our results support a pro-proliferative and pro-survival role for HOXB13 in ovarian cancer.T he HOX family of homeobox genes is an important group of developmental transcriptional regulators that are critical for various aspects of differentiation and morphogenesis (1). Similar to other genes that regulate normal growth and differentiation, HOX genes have been implicated in different aspects of the oncogenic process, because ectopic expression of HOX genes promotes cellular transformation in vitro and tumorigenesis in vivo (2). Of particular interest to human tumorigenesis is the observation that various human tumors including breast, colon, prostate, and lung carcinomas display altered HOX gene expression (3-7). Several HOX family members have been implicated in ovarian cancer differentiation (8, 9), although it is unknown whether HOX genes play a direct role in ovarian cancer progression.We recently demonstrated that dysregulated HOXB13 expression in human breast cancer is directly correlated with poor clinical outcome in estrogen receptor (ER)-positive breast cancer patients treated with tamoxifen monotherapy (10). In preliminary functional studies, we demonstrated that ectopic expression of HOXB13 in a nontransformed human mammary epithelial cell confers increased cell migration and invasion, two characteristics associated with tumor aggressiveness (10). Consistent with a possible role in human tumorigenesis, others have recently shown that HOXB13 is overexpressed in human endometrial, ovarian, and cervical carcinomas and that overexpression of HOXB13 is associated with the invasiveness of ovarian and endometrial cancer cells (11-13). Collectively, these observations suggest that HOXB13 may play an important role in tumors arising from endocrine-responsive organs. Herein, we characterized the expression of HOXB13 in ovarian cancer cell lines and tumors. Furthermore, we investigated the potential growth modulatory role of HOXB13 in vitro and in a genetically defined mouse mod...

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Section: Knockdown Of Endogenous Hoxb13 In Human Ovarian Cancer Cellcontrasting

confidence: 99%

HOXB13 promotes ovarian cancer progression

Miao

Wang

Provencher

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

105

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“…In addition, mice lacking Hoxb13 showed hypoplasia of the ventral prostate duct tips and did not produce secretory proteins, suggesting that Hoxb13 is required for the normal differentiation of the ventral prostate . A recent report also showed that ectopic expression of HOXB13 in a prostate cancer cell line induced G1 cell cycle arrest through negative regulation of T-cell factor-4, but did not lead to apoptotic change (Jung et al, 2004a). However, these reports did not mention the expression of HOXB13 in the kidney or renal tubular cells.…”

Section: Discussionmentioning

confidence: 98%

Epigenetic inactivation of the candidate tumor suppressor gene HOXB13 in human renal cell carcinoma

Okuda¹,

Toyota

Ishida

et al. 2005

Oncogene

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Epigenetic alterations like DNA methylation and the resulting inactivation of cancer-related genes often contribute to the development of various cancers. To identify the genes that are silenced by aberrant methylation in renal cell carcinoma (RCC), we subjected two RCC lines to methylated CpG island amplification/representational difference analysis. This identified 27 CpG islands. Combined bisulfite restriction analysis of these CpG islands in primary RCC cases revealed that four were methylated in a tumor-specific manner. One of these was identified as the human homeo-box gene B13 (HOXB13) gene, but the remaining three CpG islands were not associated with known genes. The methylation frequencies of HOXB13 in primary RCC samples and lines were 30 and 73%, respectively. The methylation status of HOXB13 correlated with the loss of its expression both in RCC lines and primary tumors, and methyltransferase inhibitor treatment induced the recovery of its expression. Exogenous expression of HOXB13 in RCC cells that lacked endogenous HOXB13 expression suppressed colony formation and induced apoptotic features. Furthermore, HOXB13 methylation correlated positively with tumor grade and microvessel invasion. These results suggest that HOXB13 is a novel candidate tumor suppressor gene in RCC and that its inactivation may play an important role in both RCC tumorigenesis and progression.

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“…In human cutaneous malignant melanoma with distant metastasis, the expression level of certain HOX genes, including HOXB13, was higher than in those melanoma patients without metastases [23], and in endometrial cancer cells, antisense-transfection of the HOXB13 gene reduced the invasive ability of the cells [19]. In contrast, overexpression of HOXB13 in prostate cancer cells resulted in inhibition of cell growth and suppression of hormone-activated androgen receptor transcriptional activity, presumably via physical interaction with the receptor [24,25]. In the same study it was seen that estradiol-stimulated ER activity in breast cancer cells was not suppressed by HOXB13; in fact, if there was any influence on the activity it appears as though HOXB13 enhanced this activity [25].…”

Section: Discussionmentioning

confidence: 98%