Role of homeobox genes in the patterning, specification, and differentiation of ectodermal appendages in mammals

Duverger, Olivier; Morasso, María I.

doi:10.1002/jcp.21491

Cited by 90 publications

(62 citation statements)

References 115 publications

(139 reference statements)

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“…[35][36][37] Hence, it is likely that the proper expression of specific homeobox genes (including HOXD3) is crucial for the maintenance of a differentiated tissue phenotype, which is concordant with the role that homeobox genes have in the development of tissuespecific architecture. 38,39 However, an alternative to this would be that HOXD3 methylation may be an epiphenomenon of these processes instead of a cause. Future work is necessary to address this issue.…”

Section: Discussionmentioning

confidence: 99%

DNA methylation of HOXD3 as a marker of prostate cancer progression

Kron

Liu

Pethe

et al. 2010

Laboratory Investigation

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DNA methylation in gene promoters causes gene silencing and is a common event in cancer development and progression. The ability of aberrant methylation events to serve as diagnostic and prognostic markers is being appreciated for many cancers, including prostate cancer. Using quantitative MethyLight technology, we evaluated the relationship between HOXD3 methylation and clinicopathological parameters including biochemical recurrence, pathological stage, Gleason score (GS), and Gleason pattern in a series of 232 radical prostatectomies performed between 1998 and 2001. HOXD3 methylation was significantly greater in GS 7 cancers vs GSr6 cancers (P-value o0.001) as well as pT3/pT4 vs pT2 cancers (P-value o0.001). The proportion of cases with high methylation in GS 7 vs rGS 6 and pT3/pT4 vs pT2 were also significantly different (P-values ¼ 0.002 and 0.005, respectively). There were also significant increases in methylation from Gleason pattern 2-3 and from pattern 3 to 4/5 (paired t-test P-values ¼ 0.01 and o0.001, respectively), whereas methylation from lymph node metastases was decreased when compared with matched tumor tissue (P-value ¼ 0.029). HOXD3 methylation was associated with biochemical recurrence in univariate analysis (P-value ¼ 0.043) and showed evidence for interaction with pathological stage as a predictor variable in Cox regression analysis (P-value ¼ 0.028). The results indicate that HOXD3 methylation distinguishes low-grade prostate cancers from intermediate and high-grade ones and may also have prognostic value when considered together with pathological stage.

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Section: Discussionmentioning

confidence: 99%

DNA methylation of HOXD3 as a marker of prostate cancer progression

Kron

Liu

Pethe

et al. 2010

Laboratory Investigation

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“…7A). Hairs and feathers are other skinderived appendages whose early development shares similarities with MP induction and invagination (58)(59)(60)(61). Of note, they also express different Hox gene combinations (32)(33)(34)62).…”

Section: Discussionmentioning

confidence: 99%

Control of Hoxd gene transcription in the mammary bud by hijacking a preexisting regulatory landscape

Schep

Necşulea

Rodríguez-Carballo

et al. 2016

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

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Vertebrate Hox genes encode transcription factors operating during the development of multiple organs and structures. However, the evolutionary mechanism underlying this remarkable pleiotropy remains to be fully understood. Here, we show that Hoxd8 and Hoxd9, two genes of the HoxD complex, are transcribed during mammary bud (MB) development. However, unlike in other developmental contexts, their coexpression does not rely on the same regulatory mechanism. Hoxd8 is regulated by the combined activity of closely located sequences and the most distant telomeric gene desert. On the other hand, Hoxd9 is controlled by an enhancer-rich region that is also located within the telomeric gene desert but has no impact on Hoxd8 transcription, thus constituting an exception to the global regulatory logic systematically observed at this locus. The latter DNA region is also involved in Hoxd gene regulation in other contexts and strongly interacts with Hoxd9 in all tissues analyzed thus far, indicating that its regulatory activity was already operational before the appearance of mammary glands. Within this DNA region and neighboring a strong limb enhancer, we identified a short sequence conserved in therian mammals and capable of enhancer activity in the MBs. We propose that Hoxd gene regulation in embryonic MBs evolved by hijacking a preexisting regulatory landscape that was already at work before the emergence of mammals in structures such as the limbs or the intestinal tract.enhancers | TAD | mammalian development | mammary gland

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“…HOX expression is frequently perturbed in tumors (3), in which they can act as oncogenes by promoting cell growth and invasion (4,5) or as tumor suppressors (TSs), because they can alter cell survival and morphogenesis (6)(7)(8)(9). HOX genes are especially important in the mammary gland, which undergoes repeated rounds of developmental cycles in the adult organism (10,11). In the breast, HOX genes have been implicated in the control of embryonic development, branching morphogenesis, and hormonally controlled differentiation (10,12), and HOX genes are frequently lost or overexpressed in breast tumors (12).…”

Section: Introductionmentioning

confidence: 99%

HOXA9 regulates BRCA1 expression to modulate human breast tumor phenotype

Gilbert¹,

Mouw²,

Unger³

et al. 2010

J. Clin. Invest.

103

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Breast cancer 1, early onset (BRCA1) expression is often reduced in sporadic breast tumors, even in the absence of BRCA1 genetic modifications, but the molecular basis for this is unknown. In this study, we identified homeobox A9 (HOXA9) as a gene frequently downregulated in human breast cancers and tumor cell lines and noted that reduced HOXA9 transcript levels associated with tumor aggression, metastasis, and patient mortality. Experiments revealed that loss of HOXA9 promoted mammary epithelial cell growth and survival and perturbed tissue morphogenesis. Restoring HOXA9 expression repressed growth and survival and inhibited the malignant phenotype of breast cancer cells in culture and in a xenograft mouse model. Molecular studies showed that HOXA9 restricted breast tumor behavior by directly modulating the expression of BRCA1. Indeed, ectopic expression of wild-type BRCA1 phenocopied the tumor suppressor function of HOXA9, and reducing BRCA1 levels or function inhibited the antitumor activity of HOXA9. Consistently, HOXA9 expression correlated with BRCA1 in clinical specimens and with tumor aggression in patients lacking estrogen receptor/progesterone receptor expression in their breast tissue. These findings indicate that HOXA9 restricts breast tumor aggression by modulating expression of the tumor suppressor gene BRCA1, which we believe provides an explanation for the loss of BRCA1 expression in sporadic breast tumors in the absence of BRCA1 genetic modifications.

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Role of homeobox genes in the patterning, specification, and differentiation of ectodermal appendages in mammals

Cited by 90 publications

References 115 publications

DNA methylation of HOXD3 as a marker of prostate cancer progression

DNA methylation of HOXD3 as a marker of prostate cancer progression

Control of Hoxd gene transcription in the mammary bud by hijacking a preexisting regulatory landscape

HOXA9 regulates BRCA1 expression to modulate human breast tumor phenotype

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