**3.2 The HOX proteins**

The HOX proteins encoded by the homeobox genes are DNA binding transcription factors known to regulate embryonic development. In addition, the *HOX* genes are dynamically expressed in the endometrium during the menstrual cycle, where they are necessary for endometrial growth, differentiation, and implantation (Cakmak & Taylor, 2010; Zanatta et al., 2010). Furthermore, HOX proteins are molecular mediators of the steroid hormones during endometrial cell development.

It has been suggested that a HOX gene-related defect in endometrial development exists in patients with endometriosis (Zanatta et al., 2010). According to this theory, endometriosis might originate from estrogen stimulated metaplasia of mesenchymal embryonic cells distributed in the pelvis during organogenesis. However, transcriptional dysregulation of the HOX genes in the adult endometrium compatible with the more well-supported retrograde menstruation pathogenesis model is also well substantiated. Recently, a systematic dysregulation of *HOX* genes in the endometrium from healthy women compared with the endometrium in women with endometriosis has been demonstrated (Borghese et al., 2008). A down-regulation of *HOXA* and *HOXB* genes and an up-regulation of HOXC genes were found in endometrium from women with endometriosis compared with endometrium from healthy women.

The HOXA10 protein is up-regulated in response to circulating estrogen and progesterone in the healthy endometrium, thus indicating a role in endometrial maturation, implantation and maintenance of pregnancy implantation (Cakmak & Taylor, 2010; Zanatta et al., 2010). *HOXA10* transcription is normally up-regulated in the endometrium during the window of implantation but this up-regulation is abolished in women with endometriosis. Low levels of HOXA10 could explain the lower fertility of women with endometriosis, and this is further supported by studies of the HOXA10 knock-out mice, in which the targeted disruption of the *HOXA10* gene generated uterine factor infertility. Also in the endometriotic tissue, the HOXA10 transcriptional levels were found to be low (Langendonckt et al., 2010). The endometrial down-regulation of HOXA10 protein in women with endometriosis seems to be due to increased methylation of the *HOXA10* genomic enhancer region in the endometrium leading to epigenetic silencing of this gene (reviewed in Cakmak & Taylor, 2010). In conclusion, low levels of HOXA10 may result in resistance to progesterone action in the endometriotic tissue.

*HOXB2* is part of the *HOX* gene family involved mainly in embryonic development. A very solid down-regulation of *HOXB2* in endometriotic lesions compared with endometrium from both endometriosis and healthy women has been observed (Vestergaard et al., 2011). Little is known about *HOXB2* expression in the endometrium, but several studies have demonstrated that *HOXB2* expression is altered in tumours. In a xenograft breast tumour mouse model, HOXB2 acts as a negative tumour growth regulator, since *HOXB2* expression decreases proliferation of tumour cells (Boimel et al., 2011). Other results have shown that overexpression of HOXB2 in pancreatic, lung and cervical cancer was associated with malignancy. However, a more in-depth analysis correlated lower HOXB2 expression with higher grades of tumours. Finally, it has been reported that the HOXB2 protein binds the interferon-induced protein p205, involved in the growth inhibitory activities of interferon (see Vestergaard et al., 2011). Whether HOXB2 interaction with p205 modifies the growth inhibitory activities of p205 has not yet been investigated. Further studies are needed to determine the mechanism and implications of the abolished *HOXB2* expression in endometriosis lesions.
