The orphan nuclear receptor LRH-1 promotes breast cancer motility and invasion

Chand, Ashwini L.; Herridge, Kerrie A.; Thompson, Erik W.; Clyne, Colin

doi:10.1677/erc-10-0179

Cited by 89 publications

(77 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Interestingly, NTF3 has also been shown to increase resistance to anoikis (33). LRH-1 as well has recently been implicated in pancreatic-cancer metastasis and breast-cancer development; these findings may demonstrate similar molecular underpinnings between cancer metastases (14,34,35). Another Rho member in our dataset that promotes metastasis in gastroenterological cancers is semaphorin 5A.…”

Section: Antiproliferative Mechanism Of Lrh-1 Inhibition Is Conservedsupporting

confidence: 52%

Silencing LRH-1 in colon cancer cell lines impairs proliferation and alters gene expression programs

Bayrer

Mukkamala

Sablin

et al. 2015

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

View full text Add to dashboard Cite

Colorectal cancers (CRCs) account for nearly 10% of all cancer deaths in industrialized countries. Recent evidence points to a central role for the nuclear receptor liver receptor homolog-1 (LRH-1) in intestinal tumorigenesis. Interaction of LRH-1 with the Wnt/β-catenin pathway, highly active in a critical subpopulation of CRC cells, underscores the importance of elucidating LRH-1's role in this disease. Reduction of LRH-1 diminishes tumor burden in murine models of CRC; however, it is not known whether LRH-1 is required for tumorigenesis, for proliferation, or for both. In this work, we address this question through shRNA-mediated silencing of LRH-1 in established CRC cell lines. LRH-1 mRNA knockdown results in significantly impaired proliferation in a cell line highly expressing the receptor and more modest impairment in a cell line with moderate LRH-1 expression. Cell-cycle analysis shows prolongation of G0/G1 with LRH-1 silencing, consistent with LRH-1 cellcycle influences in other tissues. Cluster analysis of microarray gene expression demonstrates significant genome wide alterations with major effects in cell-cycle regulation, signal transduction, bile acid and cholesterol metabolism, and control of apoptosis. This study demonstrates a critical proproliferative role for LRH-1 in established colon cancer cell lines. LRH-1 exerts its effects via multiple signaling networks. Our results suggest that selected CRC patients could benefit from LRH-1 inhibitors.C olorectal cancer (CRC) accounts for nearly 10% of all cancer deaths in the United States. Much is understood about maintenance, but little is known about molecules driving initiation or metastasis of CRCs. Recent discoveries in animal and cellular models of CRC suggest a role for the nuclear receptor liver receptor homolog-1 (LRH-1, also known as NR5A2) (1).LRH-1, previously thought to be constitutively active, has a functional hormone-binding pocket that binds phosphatidylcholines (2, 3). The structure of the hormone-binding domain of LRH-1 has been determined with four different phospholipids in the binding pocket (4-6).LRH-1 is vital; knockout mouse embryos fail to undergo gastrulation (7). LRH-1 is expressed in the adult in the gastrointestinal tract, including liver and pancreas, and is also present in ovaries, where it regulates steroidogenesis (8). It is highly expressed in intestinal crypts where it is believed to play a role in intestinal epithelial cell renewal (9). LRH-1 has prominent roles in development, metabolism, stem-cell pluripotency, and tumorigenesis (10-14).LRH-1 figures prominently in WNT signaling in the intestine (9, 13). The WNT gene family is a large, conserved signaling pathway with roles in development, cellular homeostasis, and tumorigenesis (15). WNT signaling activates β-catenin, an important transcriptional coactivator that is active in over 80% of CRCs (16). LRH-1 physically binds to β-catenin and functions synergistically in the regulation of certain target genes, including cyclin E1 (9).LRH-1 and β-catenin contribute to ...

show abstract

Section: Antiproliferative Mechanism Of Lrh-1 Inhibition Is Conservedsupporting

confidence: 52%

Silencing LRH-1 in colon cancer cell lines impairs proliferation and alters gene expression programs

Bayrer

Mukkamala

Sablin

et al. 2015

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

View full text Add to dashboard Cite

show abstract

“…Further work will be required to establish the mechanism responsible for this cooperation. Despite this close link between LRH-1 and ERa, it was also found that LRH-1 is expressed in ERa-negative breast cancer cells in which it controlled cell migration and invasion (20,49), suggesting that LRH-1 may also have an important role in hormone-independent cancers.…”

Section: Discussionmentioning

confidence: 99%

“…In breast cancer, LRH-1 is highly expressed and localized in the epithelial compartment of both invasive ductal carcinoma and ductal carcinoma in situ (18,19). Interestingly, depletion of LRH-1 in breast cancer cells decreases cell mobility, invasion and colony formation (20). Moreover, an important crosstalk seems to exist in estrogendependent breast cancer cells, in which LRH-1 is itself regulated by ERa (18).…”

Section: Introductionmentioning

confidence: 99%

LRH-1 Governs Vital Transcriptional Programs in Endocrine-Sensitive and -Resistant Breast Cancer Cells

Bianco

Brunelle²,

Jangal

et al. 2014

Cancer Research

View full text Add to dashboard Cite

Tumor characteristics are decisive in the determination of treatment strategy for patients with breast cancer. Patients with estrogen receptor a (ERa)-positive breast cancer can benefit from long-term hormonal treatment. Nonetheless, the majority of patients will develop resistance to these therapies. Here, we investigated the role of the nuclear receptor liver receptor homolog-1 (LRH-1, NR5A2) in antiestrogen-sensitive and -resistant breast cancer cells. We identified genome-wide LRH-1-binding sites using ChIP-seq (chromatin immunoprecipitation sequencing), uncovering preferential binding to regions distal to transcriptional start sites. We further characterized these LRH-1-binding sites by integrating overlapping layers of specific chromatin marks, revealing that many LRH-1-binding sites are active and could be involved in long-range enhancer-promoter looping. Combined with transcriptome analysis of LRH-1-depleted cells, these results show that LRH-1 regulates specific subsets of genes involved in cell proliferation in antiestrogen-sensitive and antiestrogen-resistant breast cancer cells. Furthermore, the LRH-1 transcriptional program is highly associated with a signature of poor outcome and high-grade breast cancer tumors in vivo. Herein, we report the genome-wide location and molecular function of LRH-1 in breast cancer cells and reveal its therapeutic potential for the treatment of breast cancers, notably for tumors resistant to treatments currently used in therapies. Cancer Res; 74(7); 2015-25. Ó2014 AACR.

show abstract

“…Simpson and coworkers first reported high expression of LRH-1 in preadipocytes, and they associated LRH-1 expression with transcriptional activation of CYP19 (Clyne et al, 2002). In addition to aromatase regulation, LRH-1 was shown to contribute to cancer progression by promoting motility and cell invasiveness of estrogen receptor (ER)-positive and ER-negative breast cancer cell lines (Chand et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Antiproliferation Activity of a Small Molecule Repressor of Liver Receptor Homolog 1

et al. 2014

View full text Add to dashboard Cite

The orphan nuclear receptor liver receptor homolog 1 (LRH-1; NR5A2) is a potent regulator of cholesterol metabolism and bile acid homeostasis. Recently, LRH-1 has been shown to play an important role in intestinal inflammation and in the progression of estrogen receptor positive and negative breast cancers and pancreatic cancer. Structural studies have revealed that LRH-1 can bind phospholipids and the dietary phospholipid dilauroylphosphatidylcholine activates LRH-1 activity in rodents. Here we characterize the activity of a novel synthetic nonphospholipid small molecule repressor of LRH-1, SR1848 (6-[4-(3-chlorophenyl) piperazin-1-yl]-3-cyclohexyl-1H-pyrimidine-2,4-dione). In cotransfection studies, SR1848 reduced LRH-1-dependent expression of a reporter gene and in cells that endogenously express LRH-1 dose dependently reduced the expression of cyclin-D1 and -E1, resulting in inhibition of cell proliferation. The cellular effects of SR1848 treatment are recapitulated after transfection of cells with small-interfering RNA targeting LRH-1. Immunocytochemistry analysis shows that SR1848 induces rapid translocation of nuclear LRH-1 to the cytoplasm. Combined, these results suggest that SR1848 is a functional repressor of LRH-1 that impacts expression of genes involved in proliferation in LRH-1-expressing cancers. Thus, SR1848 represents a novel chemical scaffold for the development of therapies targeting malignancies driven by LRH-1.

show abstract

The orphan nuclear receptor LRH-1 promotes breast cancer motility and invasion

Cited by 89 publications

References 47 publications

Silencing LRH-1 in colon cancer cell lines impairs proliferation and alters gene expression programs

Silencing LRH-1 in colon cancer cell lines impairs proliferation and alters gene expression programs

LRH-1 Governs Vital Transcriptional Programs in Endocrine-Sensitive and -Resistant Breast Cancer Cells

Antiproliferation Activity of a Small Molecule Repressor of Liver Receptor Homolog 1

Contact Info

Product

Resources

About