DLC1: a tumor suppressor that regulates Rho signaling

Tripathi, Brajendra K.; Lowy, Douglas R.

doi:10.18632/oncotarget.16805

Cited by 4 publications

(2 citation statements)

References 7 publications

(10 reference statements)

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“…S2 E and F). Because DLC1 has been previously reported by others as a tumor suppressor in multiple solid tumors, it was hypothesized that DLC1 may have an E2-induced tumor suppressor function in these normal breast epithelial cells (10)(11)(12)(13)(14). When DLC1 was silenced by siRNA in the luminal ER + breast cancer cell line MCF-7, a proproliferative phenotype was observed with almost a doubling in the rate of E2-induced cellular proliferation compared with the control siRNA ( Fig.…”

Section: Estrogen Stimulation Induces Differential Transcriptional Rementioning

confidence: 84%

Estrogen receptor signaling is reprogrammed during breast tumorigenesis

Chi

Singhal

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Limited knowledge of the changes in estrogen receptor (ER) signaling during the transformation of the normal mammary gland to breast cancer hinders the development of effective prevention and treatment strategies. Differences in estrogen signaling between normal human primary breast epithelial cells and primary breast tumors obtained immediately following surgical excision were explored. Transcriptional profiling of normal ER + mature luminal mammary epithelial cells and ER + breast tumors revealed significant difference in the response to estrogen stimulation. Consistent with these differences in gene expression, the normal and tumor ER cistromes were distinct and sufficient to segregate normal breast tissues from breast tumors. The selective enrichment of the DNA binding motif GRHL2 in the breast cancerspecific ER cistrome suggests that it may play a role in the differential function of ER in breast cancer. Depletion of GRHL2 resulted in altered ER binding and differential transcriptional responses to estrogen stimulation. Furthermore, GRHL2 was demonstrated to be essential for estrogen-stimulated proliferation of ER + breast cancer cells. DLC1 was also identified as an estrogen-induced tumor suppressor in the normal mammary gland with decreased expression in breast cancer. In clinical cohorts, loss of DLC1 and gain of GRHL2 expression are associated with ER + breast cancer and are independently predictive for worse survival. This study suggests that normal ER signaling is lost and tumor-specific ER signaling is gained during breast tumorigenesis. Unraveling these changes in ER signaling during breast cancer progression should aid the development of more effective prevention strategies and targeted therapeutics.breast cancer | estrogen receptor | mammary gland | cancer genomics | tumorigenesis

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Section: Estrogen Stimulation Induces Differential Transcriptional Rementioning

confidence: 84%

Estrogen receptor signaling is reprogrammed during breast tumorigenesis

Chi

Singhal

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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“…DLC1 is a tumor suppressor gene that is down-regulated in a variety of cancers through genetic and epigenetic modifications. The DLC1 protein possesses a Rho-GTPaseactivating protein (GAP) activity, which negatively regulates RhoA-GTP (3,4). RhoA-GTP is involved in several cell biological processes such as proliferation, migration, and cytokinesis and is frequently activated in advanced cancer, contributing to the maintenance of the oncogenic phenotype.…”

Section: What Are You Currently Working On?mentioning

confidence: 99%

Brajendra Tripathi: Keeping an eye out for translational research

O’Donnell¹

2019

Journal of Cell Biology

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High expression of SMARCA4 or SMARCA2 is frequently associated with an opposite prognosis in cancer

Guerrero-Martínez

Reyes

2018

Sci Rep

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The gene encoding the ATPase of the chromatin remodeling SWI/SNF complexes SMARCA4 (BRG1) is often mutated or silenced in tumors, suggesting a role as tumor suppressor. Nonetheless, recent reports show requirement of SMARCA4 for tumor cells growth. Here, we performed a computational meta-analysis using gene expression, prognosis, and clinicopathological data to clarify the role of SMARCA4 and the alternative SWI/SNF ATPase SMARCA2 (BRM) in cancer. We show that while the SMARCA4 gene is mostly overexpressed in tumors, SMARCA2 is almost invariably downexpressed in tumors. High SMARCA4 expression was associated with poor prognosis in many types of tumors, including liver hepatocellular carcinoma (LIHC), and kidney renal clear cell carcinoma (KIRC). In contrast, high SMARCA2 expression was associated with good prognosis. We compared tumors with high versus low expression of SMARCA4 or SMARCA2 in LIHC and KIRC cohorts from The Cancer Genome Atlas. While a high expression of SMARCA4 is associated with aggressive tumors, a high expression of SMARCA2 is associated with benign differentiated tumors, suggesting that SMARCA4 and SMARCA2 play opposite roles in cancer. Our results demonstrate that expression of SMARCA4 and SMARCA2 have a high prognostic value and challenge the broadly accepted general role of SMARCA4 as a tumor suppressor.

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DLC1: a tumor suppressor that regulates Rho signaling

Cited by 4 publications

References 7 publications

Estrogen receptor signaling is reprogrammed during breast tumorigenesis

Estrogen receptor signaling is reprogrammed during breast tumorigenesis

Brajendra Tripathi: Keeping an eye out for translational research

High expression of SMARCA4 or SMARCA2 is frequently associated with an opposite prognosis in cancer

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