The Inhibitory Effect of Aryl Hydrocarbon Receptor Repressor (AhRR) on the Growth of Human Breast Cancer MCF-7 Cells

Kanno, Yuichiro; Takane, Yusuke; Izawa, Tomomi; Nakahama, Takayuki; Inouye, Yoshio

doi:10.1248/bpb.29.1254

Cited by 22 publications

(18 citation statements)

References 25 publications

(14 reference statements)

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“…Such broad interactions are consistent with the emerging view of AHRR as an important regulatory protein with pleiotropic effects on cell growth and differentiation, including a possible role as a tumor suppressor (22,30,56,68,71). Understanding these interactions of the hAHRR and their biological significance will be an important goal of future research.…”

Section: Discussionsupporting

confidence: 76%

“…A human AHRR (hAHRR) Ala185Pro polymorphism has been associated with altered reproductive development and infertility in men (16,46,59,64) and endometriosis in women (19,35,62,65), but the functional properties of the polymorphic variants have never been assessed. AHRR overexpression inhibits the growth of human tumor cells in culture (30,56,68). Conversely, knockdown of AHRR expression enhances cell growth and confers resistance to apoptosis; consistent with this, the AHRR gene has been found to be silenced by hypermethylation in a variety of human cancers (71).…”

mentioning

confidence: 55%

“…However, in the few studies to examine the function of the hAHRR protein, it has not always been clear which form was being investigated (21,29,30,71). The substantial difference in repressor activity between the two forms described here (Fig.…”

Section: Discussionmentioning

confidence: 91%

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The Active Form of Human Aryl Hydrocarbon Receptor (AHR) Repressor Lacks Exon 8, and Its Pro¹⁸⁵ and Ala¹⁸⁵ Variants Repress both AHR and Hypoxia-Inducible Factor

Karchner

Jenny

Tarrant

et al. 2009

Molecular and Cellular Biology

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The aryl hydrocarbon receptor (AHR) repressor (AHRR) inhibits AHR-mediated transcription and has been associated with reproductive dysfunction and tumorigenesis in humans. Previous studies have characterized the repressor function of AHRRs from mice and fish, but the human AHRR ortholog (AHRR 715 ) appeared to be nonfunctional in vitro. Here, we report a novel human AHRR cDNA (AHRR⌬8) that lacks exon 8 of AHRR 715 . AHRR⌬8 was the predominant AHRR form expressed in human tissues and cell lines. AHRR⌬8 effectively repressed AHR-dependent transactivation, whereas AHRR 715 was much less active. Similarly, AHRR⌬8, but not AHRR 715 , formed a complex with AHR nuclear translocator (ARNT). Repression of AHR by AHRR⌬8 was not relieved by overexpression of ARNT or AHR coactivators, suggesting that competition for these cofactors is not the mechanism of repression. AHRR⌬8 interacted weakly with AHR but did not inhibit its nuclear translocation. In a survey of transcription factor specificity, AHRR⌬8 did not repress the nuclear receptor pregnane X receptor or estrogen receptor ␣ but did repress hypoxia-inducible factor (HIF)-dependent signaling. AHRR⌬8-Pro 185 and -Ala 185 variants, which have been linked to human reproductive disorders, both were capable of repressing AHR or HIF. Together, these results identify AHRR⌬8 as the active form of human AHRR and reveal novel aspects of its function and specificity as a repressor.

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Section: Discussionsupporting

confidence: 76%

mentioning

confidence: 55%

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The Active Form of Human Aryl Hydrocarbon Receptor (AHR) Repressor Lacks Exon 8, and Its Pro¹⁸⁵ and Ala¹⁸⁵ Variants Repress both AHR and Hypoxia-Inducible Factor

Karchner

Jenny

Tarrant

et al. 2009

Molecular and Cellular Biology

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“…Artificial upregulation of AHRR results in impaired anchorage-dependent and -independent growth. In agreement with these data, a recent report shows that overexpression of AHRR results in blockade of growth in the breast cancer cell line MCF-7 (18). Interestingly, partial silencing of AHRR in nontumoral MCF10A (which lack the ability of anchorage-independent growth; ref.…”

Section: Figuresupporting

confidence: 76%

“…The role of AHRR in carcinogenesis has not been extensively explored. Overexpression of AHRR in the breast cancer cell line MCF-7 results in growth inhibition (18) and genetic polymorphisms in AHRR are related to susceptibility to advanced endometriosis (19). Here we provide clinical, genetic, and functional evidence from in vitro and in vivo experiments supporting a critical role of AHRR as a putative tumor suppressor gene in several types of human cancer.…”

Section: Introductionmentioning

confidence: 71%

The aryl hydrocarbon receptor repressor is a putative tumor suppressor gene in multiple human cancers

Zudaire¹,

Cuesta²,

Murty³

et al. 2008

J. Clin. Invest.

148

169

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The aryl hydrocarbon receptor repressor (AHRR) is a bHLH/Per-ARNT-Sim transcription factor located in a region of chromosome 5 (5p15.3) that has been proposed to contain one or more tumor suppressor genes. We report here consistent downregulation of AHRR mRNA in human malignant tissue from different anatomical origins, including colon, breast, lung, stomach, cervix, and ovary, and demonstrate DNA hypermethylation as the regulatory mechanism of AHRR gene silencing. Knockdown of AHRR gene expression in a human lung cancer cell line using siRNA significantly enhanced in vitro anchorage-dependent and -independent cell growth as well as cell growth after transplantation into immunocompromised mice. In addition, knockdown of AHRR in non-clonable normal human mammary epithelial cells enabled them to grow in an anchorage-independent manner. Further, downregulation of AHRR expression in the human lung cancer cell line conferred resistance to apoptotic signals and enhanced motility and invasion in vitro and angiogenic potential in vivo. Ectopic expression of AHRR in tumor cells resulted in diminished anchorage-dependent and -independent cell growth and reduced angiogenic potential. These results therefore demonstrate that AHRR is a putative new tumor suppressor gene in multiple types of human cancers.

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Regulation of AHR Activity by the AHR Repressor (AHRR)

Fujii‐Kuriyama

Kawajiri

2011

The AH Receptor in Biology and Toxicology

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The Inhibitory Effect of Aryl Hydrocarbon Receptor Repressor (AhRR) on the Growth of Human Breast Cancer MCF-7 Cells

Cited by 22 publications

References 25 publications

The Active Form of Human Aryl Hydrocarbon Receptor (AHR) Repressor Lacks Exon 8, and Its Pro¹⁸⁵ and Ala¹⁸⁵ Variants Repress both AHR and Hypoxia-Inducible Factor

The Active Form of Human Aryl Hydrocarbon Receptor (AHR) Repressor Lacks Exon 8, and Its Pro¹⁸⁵ and Ala¹⁸⁵ Variants Repress both AHR and Hypoxia-Inducible Factor

The aryl hydrocarbon receptor repressor is a putative tumor suppressor gene in multiple human cancers

Regulation of AHR Activity by the AHR Repressor (AHRR)

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The Inhibitory Effect of Aryl Hydrocarbon Receptor Repressor (AhRR) on the Growth of Human Breast Cancer MCF-7 Cells

Cited by 22 publications

References 25 publications

The Active Form of Human Aryl Hydrocarbon Receptor (AHR) Repressor Lacks Exon 8, and Its Pro185 and Ala185 Variants Repress both AHR and Hypoxia-Inducible Factor

The Active Form of Human Aryl Hydrocarbon Receptor (AHR) Repressor Lacks Exon 8, and Its Pro185 and Ala185 Variants Repress both AHR and Hypoxia-Inducible Factor

The aryl hydrocarbon receptor repressor is a putative tumor suppressor gene in multiple human cancers

Regulation of AHR Activity by the AHR Repressor (AHRR)

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The Active Form of Human Aryl Hydrocarbon Receptor (AHR) Repressor Lacks Exon 8, and Its Pro¹⁸⁵ and Ala¹⁸⁵ Variants Repress both AHR and Hypoxia-Inducible Factor

The Active Form of Human Aryl Hydrocarbon Receptor (AHR) Repressor Lacks Exon 8, and Its Pro¹⁸⁵ and Ala¹⁸⁵ Variants Repress both AHR and Hypoxia-Inducible Factor