Loss of REST in breast cancer promotes tumor progression through estrogen sensitization, MMP24 and CEMIP overexpression.

Autor: Cloud AS; Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS, USA., Vargheese AM; Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS, USA.; The University of Kansas Cancer Center, Kansas City, KS, USA.; University of Kansas, Lawrence, KS, USA., Gunewardena S; Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS, USA.; Department of Biostatistics, University of Kansas Medical Center, Kansas City, KS, USA., Shimak RM; The University of Kansas Cancer Center, Kansas City, KS, USA.; Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA., Ganeshkumar S; Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS, USA., Kumaraswamy E; The University of Kansas Cancer Center, Kansas City, KS, USA.; Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA., Jensen RA; The University of Kansas Cancer Center, Kansas City, KS, USA.; University of Kansas, Lawrence, KS, USA.; Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA.; Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, USA.; Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS, USA., Chennathukuzhi VM; Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS, USA. vchennathukuzhi@kumc.edu.; The University of Kansas Cancer Center, Kansas City, KS, USA. vchennathukuzhi@kumc.edu.
Jazyk: angličtina
Zdroj: BMC cancer [BMC Cancer] 2022 Feb 17; Vol. 22 (1), pp. 180. Date of Electronic Publication: 2022 Feb 17.
DOI: 10.1186/s12885-022-09280-2
Abstrakt: Background: Breast cancer is the most common malignancy in women, and is both pathologically and genetically heterogeneous, making early detection and treatment difficult. A subset of breast cancers express normal levels of REST (repressor element 1 silencing transcription factor) mRNA but lack functional REST protein. Loss of REST function is seen in ~ 20% of breast cancers and is associated with a more aggressive phenotype and poor prognosis. Despite the frequent loss of REST, little is known about the role of REST in the molecular pathogenesis of breast cancer.
Methods: TCGA data was analyzed for the expression of REST target genes in breast cancer patient samples. We then utilized gene knockdown in MCF-7 cells in the presence or absence of steroid hormones estrogen and/ progesterone followed by RNA sequencing, as well as chromatin immunoprecipitation and PCR in an attempt to understand the tumor suppressor role of REST in breast cancer.
Results: We show that REST directly regulates CEMIP (cell migration-inducing and hyaluronan-binding protein, KIAA1199) and MMP24 (matrix metallopeptidase 24), genes known to have roles in invasion and metastasis. REST knockdown in breast cancer cells leads to significant upregulation of CEMIP and MMP24. In addition, we found REST binds to RE-1 sites (repressor element-1) within the genes and influences their transcription. Furthermore, we found that the estrogen receptor (ESR1) signaling pathway is activated in the absence of REST, regardless of hormone treatment.
Conclusions: We demonstrate a critical role for the loss of REST in aggressive breast cancer pathogenesis and provide evidence for REST as an important diagnostic marker for personalized treatment plans.
(© 2022. The Author(s).)
Databáze: MEDLINE
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