Abstract
Abstract Background: Disruption of tissue polarity is one of hallmarks of breast cancer development, which is associated with cell invasion and cancer dissemination. Therefore, identifying proteins and pathways that modulate cell polarity is crucial not only to advancing our knowledge of breast cancer, but also to discovering potential therapeutic targets. Methods: To identify potential regulators of tissue polarity, we analyzed over-represented DNA motifs in the promoter regions of the polarization genes that are significantly up-regulated genes in polarized human mammary epithelial cells in a physiologically relevant three-dimensional (3D) culture system. We assessed the protein levels of RORα by immunoblotting and immunohistochemistry in malignant and non-malignant human mammary epithelial cells as well as human breast cancer tissue array. To explore the functional significance of RORα down-regulation the malignance of breast cancer cells, we restored RORα expression in malignant T4-2 cells, MDA231 cells and silenced RORα expression in non-malignant S1 cells. The growth and malignant phenotypes of these cells were examined in 3D culture and xenograft model. Results: Results from promoter analysis suggest that RORα is a potential regulator of mammary tissue polarity and is inactivated in disorganized HMECs. Expression of RORα protein is significantly reduced in malignant breast cancer cell lines and this reduction is associated with disruption of acinar structure in 3D culture. Both mRNA and protein level of RORα were significantly reduced in human breast cancer tissues. Restoring RORα expression in T4-2 and MDA-MB 231 cells significantly suppressed proliferation, invasion and the malignant phenotypes in 3D culture. Silencing RORα expression in non-malignant S1 cells disrupts the polarized acinar morphogenesis. Restoring RORα expression in T4-2 and MDA-MB 231 cells also inhibits the tumor growth in nude mice. Moreover, patients with reduced expression of RORα in cancer tissue have significantly shorter survival. Conclusion: Together these results indicate that inactivation of RORα promotes the breast cancer development and progression by enhancing cell invasion and disturbing normal tissue architecture. RORα provide a potential therapeutic target for breast cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2701. doi:1538-7445.AM2012-2701
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