Abstract 4703: Role of REST in the regulation of MMP24 and estrogen sensitivity in breast cancer

Abstract

Abstract Breast cancer, the most common malignancy in women, is very difficult to detect and treat due to its heterogeneity. An important subset of breast cancers, Luminal or ER/PR positive tumors, lack REST (repressor element 1 silencing transcription factor) protein but not its mRNA. REST is a tumor suppressor and is known to play a role in regulating neurodegenerative diseases such as Alzheimer's. The loss of REST leads to the dysregulation of its target genes, many of which are involved in tumorigenesis. About 20% of breast cancers show loss of REST expression, yet little to nothing is currently known about the role REST plays in tumor growth. We hypothesized that the loss of REST promotes breast cancer growth by altering cell signaling. Our results show that knockdown of REST in MCF7 cells (ER/PR positive) causes similar gene dysregulation as seen in aggressive forms of breast cancers. Also, Ingenuity Pathway Analysis (IPA®) of our RNA sequencing results showed that REST knockdown leads to significant increase in estrogen receptor signaling in MCF7 cells. Upregulation of estrogen receptor expression has been associated with tumor progression. In addition, REST knockdown led to significant increases in the expression of MMP24 (>20-fold, p<10−85), a matrix modifying enzyme which could play a role in tumor metastasis, as well as KCNK3 (19-fold, p<10−40), a biomarker associated with poor patient survival. Thus, the poor survival of patients with RESTless breast cancers may be related to the activation of its target genes and elevated estrogen receptor signaling. Furthermore, these patients may respond differently to estrogen receptor antagonists compared to those with REST positive breast cancers. Our results will help with the future development of individualized therapies for breast cancer. Citation Format: Aditya M. Vargheese, Ashley Cloud, Sumedha Gunewardena, Raeann Shimak, Easwari Kumaraswamy, Roy A. Jensen, Vargheese M. Chennathukuzhi. Role of REST in the regulation of MMP24 and estrogen sensitivity in breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4703.