RAR agonists stimulate SOX9 gene expression in breast cancer cell lines: evidence for a role in retinoid-mediated growth inhibition

Abstract

Retinoic acid receptors (RARs) are ligand-dependent transcription factors which are members of the steroid/ thyroid hormone receptor gene family. RAR-agonists inhibit the proliferation of many human breast cancer cell lines, particularly those whose growth is stimulated by estradiol (E2) or growth factors. PCR-amplified subtractive hybridization was used to identify candidate retinoidregulated genes that may be involved in growth inhibition. One candidate gene identified was SOX9, a member of the high mobility group (HMG) box gene family of transcription factors. SOX9 gene expression is rapidly stimulated by RAR-agonists in T-47D cells and other retinoidinhibited breast cancer cell lines. In support of this finding, a database search indicates that SOX9 is expressed as an EST in breast tumor cells. SOX9 is known to be expressed in chondrocytes where it regulates the transcription of type II collagen and in testes where it plays a role in male sexual differentiation. RAR pan-agonists and the RARa-selective agonist Am580, but not RXR agonists, stimulate the expression of SOX9 in a wide variety of retinoid-inhibited breast cancer cell lines. RAR-agonists did not stimulate SOX9 in breast cancer cell lines which were not growth inhibited by retinoids. Expression of SOX9 in T-47D cells leads to cycle changes similar to those found with RARagonists while expression of a dominant negative form of SOX9 blocks RA-mediated cell cycle changes, suggesting a role for SOX9 in retinoid-mediated growth inhibition.

Identification of DNA hypermethylation of SOX9 in association with bladder cancer progression using CpG microarrays

“…Such finding meets concordance with the knowledge of the involvement of this gene in human solid neoplasias. Inactivation by hypermethylation of SOX9, a gene reported to be a potential tumour suppressor, would be justified to be a poor outcome prognosticator (Afonja et al, 2002;Wehrli et al, 2003;Drivdahl et al, 2004). Thus, the gene identified in the present work represents a novel methylated tumour suppressor candidate to be investigated in bladder cancer.…”

“…SOX9 is a transcription factor that is expressed in chondrocytes and several tissues, including the central nervous and urogenital systems Soderstrom et al, 2002). SOX9 has been shown to be relevant at distinguishing mesenchymal chondrosarcoma from other small blue round cell tumours (Soderstrom et al, 2002;Wehrli et al, 2003) and at modulating retinoid-mediated growth in breast cancer cells (Afonja et al, 2002). Growth and tumorigenicity suppression associated with SOX9 has been found in prostate, breast and colon cells (Afonja et al, 2002;Drivdahl et al, 2004;Jay et al, 2005).…”

“…SOX9 has been shown to be relevant at distinguishing mesenchymal chondrosarcoma from other small blue round cell tumours (Soderstrom et al, 2002;Wehrli et al, 2003) and at modulating retinoid-mediated growth in breast cancer cells (Afonja et al, 2002). Growth and tumorigenicity suppression associated with SOX9 has been found in prostate, breast and colon cells (Afonja et al, 2002;Drivdahl et al, 2004;Jay et al, 2005). The epigenetic silencing of SOX9 may aid understanding as to how it contributes to tumorigenesis and tumour progression in such types of neoplasias.…”

Suppression of growth and tumorigenicity in the prostate tumor cell line M12 by overexpression of the transcription factor SOX9

“…It has also been detected in breast, skin, brain, and kidney (Kent et al, 1996;Lefebvre et al, 1997;Afonja et al, 2002), but despite the implicit significance of SOX9 in male reproductive physiology, there have been no studies on its expression or activity in prostate tissue. We have found by cDNA array analysis that its production is stimulated in M12 prostate cancer cells by transfection Figure 6 Apoptosis in M12 clones.…”

MiniSOX9, a dominant-negative variant in colon cancer cells

“…SOX9 also increases apoptosis in colon tumor cells (Jay et al, 2005) and reduces cell proliferation rate, as illustrated by hyperplasia and dysplasia induced by Sox9 abrogation in the intestine epithelium (Bastide et al, 2007;Zalzali et al, 2008). The anti-proliferative activity of SOX9 was also evidenced in retinoid-treated breast cancer cell lines and melanomas (Afonja et al, 2002;Passeron et al, 2009;Muller et al, 2010). Finally, loss of SOX9 expression and promoter hypermethylation is associated with bladder cancer progression (Aleman et al, 2008).…”