Forkhead box A1 regulates prostate ductal morphogenesis and promotes epithelial cell maturation

Gao, Nan; Ishii, Kenichiro; Mirosevich, Janni; Kuwajima, Satoru; Oppenheimer, Stacey R.; Roberts, Richard L.; Jiang, Ming; Yu, Xiuping; Shappell, Scott B.; Caprioli, Richard M.; Stoffel, Markus; Hayward, Simon W.; Matusik, Robert J.

doi:10.1242/dev.01917

Cited by 168 publications

(172 citation statements)

References 70 publications

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“…FrameWorker analysis of the identified homologous sequences in human, mouse, rhesus monkey, rat, and dog confirmed the conservation of FKHD and TALE matrices. The presence of two Foxa protein binding sites in a region demonstrated to regulate urogenital sinus and prostate expression, coupled with similar reported expression patterns between Foxa1 and Hoxb13 in the urogenital sinus and prostate (29,30), suggests that Foxa1 may directly regulate Hoxb13 expression.…”

Section: Whole-mount Analyses Of Adult B13/lzsupporting

confidence: 52%

“…During prostate carcinogenesis in the human and mouse, studies suggest that expression of both genes is maintained (31,44,45). In the homozygous knockout of either Hoxb13 or Foxa1, defects are observed in luminal cell differentiation and secretory function, with a loss of some of the same major secretory products (6,30). Despite the similarities in Foxa1 and Hoxb13 expression and the in vivo evidence of FOXA1 binding to the 37-bp enhancer, it is possible that FOXA2 may also have the ability to bind to the enhancer and regulate HOXB13 expression.…”

Section: Discussionmentioning

confidence: 99%

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A FOXA1-binding enhancer regulates Hoxb13 expression in the prostate gland

McMullin

Dobi

Mutton

et al. 2009

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

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Hoxb13 is robustly transcribed in derivatives of posterior endoderm including the colon, rectum, and the prostate gland. Transcriptional activity in the prostate persists unabated under conditions of androgen deprivation and throughout the course of disease progression in a mouse prostate cancer model. To elucidate the molecular basis of prostate-restricted transcriptional activation of Hoxb13, a bacterial artificial chromosome (BAC)-based reporter gene deletion analysis was performed in transgenic mice. Two regions downstream of the Hoxb13 coding region were found to be required to support transcriptional activity in the prostate but were completely dispensable for expression in the colon and rectum. Bioinformatic analyses of one region identified a 37-bp element conserved in mammals. This element, which bears two potential binding sites for Forkhead class transcription factors, is occupied by FOXA1 in a human prostate cancer cell line. Precise replacement of this enhancer with an extended LoxP site in the context of a 218,555-bp BAC reporter nearly extinguished Hoxb13-mediated transcriptional activity in the mouse prostate. These data demonstrate that FOXA1 directly regulates HOXB13 in human prostate epithelial cells, and show that this prostate-specific regulatory mechanism is conserved in mice.androgen independent | recombineering | prostate-specific | Homeobox | Forkhead

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Section: Whole-mount Analyses Of Adult B13/lzsupporting

confidence: 52%

Section: Discussionmentioning

confidence: 99%

A FOXA1-binding enhancer regulates Hoxb13 expression in the prostate gland

McMullin

Dobi

Mutton

et al. 2009

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

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“…The transformation of mammary epithelia to gain markers of prostatic differentiation involved the establishment of unique regulatory programs that control cell fate including steroid receptors and developmental cell-specific transcription factors. Here we showed the expression of androgen-regulated prostate-specific proteins including AR, Nkx3.1 [26], and Foxa1 (HNF-3b) [28] in mammary epithelium of heterotypic tissue recombinants. Androgen receptor and Nkx3.1 are two of the earliest markers of prostatic differentiation that are expressed at low/undetectable levels in mammary gland epithelium.…”

Section: Discussionmentioning

confidence: 79%

Lineage Enforcement by Inductive Mesenchyme on Adult Epithelial Stem Cells across Developmental Germ Layers

et al. 2009

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During development, cell differentiation is accompanied by the progressive loss of pluripotent gene expression and developmental potential, although de‐differentiation in specialized cells can be induced by reprogramming strategies, indicating that transdifferentiation potential is retained in adult cells. The stromal niche provides differentiating cues to epithelial stem cells (SCs), but current evidence is restricted to tissue types within the same developmental germ layer lineage. Anticipating the use of adult SCs for tissue regeneration, we examined if stroma can enforce lineage commitment across germ layer boundaries and promote transdifferentiation of adult epithelial SCs. Here, we report tissue‐specific mesenchyme instructing epithelial cells from a different germ layer origin to express dual phenotypes. Prostatic stroma induced mammary epithelia (or enriched Lin−CD29HICD24+/MOD mammary SCs) to generate glandular epithelia expressing both prostatic and mammary markers such as steroid hormone receptors and transcription factors including Foxa1, Nkx3.1, and GATA‐3. Array data implicated Hh and Wnt pathways in mediating stromal‐epithelial interactions (validated by increased Cyclin D1 expression). Other recombinants of prostatic mesenchyme and skin epithelia, or preputial gland mesenchyme and bladder or esophageal epithelia, showed foci expressing new markers adjacent to the original epithelial differentiation (e.g., sebaceous cells within bladder urothelium), confirming altered lineage specification induced by stroma and evidence of cross‐germ layer transdifferentiation. Thus, stromal cell niche is critical in maintaining (or redirecting) differentiation in adult epithelia. In order to use adult epithelial SCs in regenerative medicine, we must additionally regulate their intrinsic properties to prevent (or enable) transdifferentiation in specified SC niches. STEM CELLS 2009;27:3032–3042

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“…Overall, it appears that AR is likely to play different cell type-specific roles in both normal and cancer cells, which are modulated by interactions with other key regulators of prostate epithelial fate. For example, Nkx3.1 negatively regulates AR transcription and signaling activity (Lei et al 2006), while genomic analyses of AR enhancerbinding sites reveal likely interactions with Nkx3.1 and FoxA1, another key transcriptional regulator of prostate epithelial differentiation (Gao et al 2005;He et al 2010). …”

Section: Ar Function and Castration Resistancementioning

confidence: 99%

Molecular genetics of prostate cancer: new prospects for old challenges

Shen¹,

Abate‐Shen²

2010

Genes Dev.

840

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Despite much recent progress, prostate cancer continues to represent a major cause of cancer-related mortality and morbidity in men. Since early studies on the role of the androgen receptor that led to the advent of androgen deprivation therapy in the 1940s, there has long been intensive interest in the basic mechanisms underlying prostate cancer initiation and progression, as well as the potential to target these processes for therapeutic intervention. Here, we present an overview of major themes in prostate cancer research, focusing on current knowledge of principal events in cancer initiation and progression. We discuss recent advances, including new insights into the mechanisms of castration resistance, identification of stem cells and tumor-initiating cells, and development of mouse models for preclinical evaluation of novel therapuetics. Overall, we highlight the tremendous research progress made in recent years, and underscore the challenges that lie ahead.

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Forkhead box A1 regulates prostate ductal morphogenesis and promotes epithelial cell maturation

Abstract: SummaryForkhead box A1 regulates prostate ductal morphogenesis and promotes epithelial cell maturation

Cited by 168 publications

References 70 publications

A FOXA1-binding enhancer regulates Hoxb13 expression in the prostate gland

A FOXA1-binding enhancer regulates Hoxb13 expression in the prostate gland

Lineage Enforcement by Inductive Mesenchyme on Adult Epithelial Stem Cells across Developmental Germ Layers

Molecular genetics of prostate cancer: new prospects for old challenges

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