Immunolocalization of liver receptor homologue-1 (LRH-1) in human breast carcinoma: Possible regulator of in situ steroidogenesis

Miki, Yasuhiro; Clyne, Colin; Suzuki, Takashi; Moriya, Takuya; Shibuya, Rie; Nakamura, Yasuhiro; Ishida, Toru; Yabuki, Nami; Kitada, Koji; Hayashi, Shin Ichi; Sasano, Hironobu

doi:10.1016/j.canlet.2005.11.038

Cited by 53 publications

(51 citation statements)

References 38 publications

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“…In breast cancer, LRH-1 stimulates aromatase expression in adipose stromal cells, thereby increasing the availability of local oestrogen for ER-positive tumour growth (Clyne et al 2002, Zhou et al 2005. However, LRH-1 is also expressed in breast cancer epithelial cells where it could potentially have direct effects, independent of aromatase (Miki et al 2006). In this study, using shRNA and overexpression strategies, we have shown that LRH-1 directly stimulates cell migration and invasion in both ER-positive and ER-negative breast cancer cell lines, as well as in the normal breast epithelial MCF-10A line.…”

Section: Discussionmentioning

confidence: 79%

“…In pre-and post-menopausal breast cancer patients, high LRH-1 protein expression is detected in invasive ductal carcinomas (43%), ductal carcinoma in situ (28%) and adipose stromal cells (Annicotte et al 2005, Zhou et al 2005, Miki et al 2006. This aberrant expression of LRH-1 in breast cancer stroma activates aromatase transcription thus increasing local oestrogen production within the tumour microenvironment (Bulun & Simpson 1994, Simpson & Davis 2001, Zhou et al 2005.…”

Section: Introductionmentioning

confidence: 99%

“…LRH-1 has been shown to be a tumour-promoting transcription factor in colon, gastric and breast cancers (Botrugno et al 2004, Schoonjans et al 2005, Miki et al 2006, Wang et al 2008. LRH-1 increases cell proliferation in murine pancreatic LTPA and hepatic FL83B cells through the induction of cyclins, D1 and E1, with co-operative recruitment of b-catenin and LRH-1 to their promoters (Botrugno et al 2004).…”

Section: Introductionmentioning

confidence: 99%

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

Chand¹,

Herridge²,

Thompson³

et al. 2010

Endocrine-Related Cancer

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The orphan nuclear receptor liver receptor homologue-1 (LRH-1) has roles in the development, cholesterol and bile acid homeostasis, and steroidogenesis. It also enhances proliferation and cell cycle progression of cancer cells. In breast cancer, LRH-1 expression is associated with invasive breast cancer; positively correlates with ERa status and aromatase activity; and promotes oestrogen-dependent cell proliferation. However, the mechanism of action of LRH-1 in breast cancer epithelial cells is still not clear. By silencing or over-expressing LRH-1 in ER-positive MCF-7 and ER-negative MDA-MB-231 breast cancer cells, we have demonstrated that LRH-1 promotes motility and cell invasiveness. Similar effects were observed in the non-tumourigenic mammary epithelial cell line, MCF-10A. Remodelling of the actin cytoskeleton and E-cadherin cleavage was observed with LRH-1 over-expression, contributing to increased migratory and invasive properties. Additionally, in LRH-1 over-expressing cells, the truncation of the 120 kDa E-cadherin to the inactive 97 kDa form was observed. These post-translational modifications in E-cadherin may be associated with LRH-1-dependent changes to matrix metalloproteinase 9 expression. These findings suggest a new role of LRH-1 in promoting migration and invasion in breast cancer, independent of oestrogen sensitivity. Therefore, LRH-1 may represent a new target for breast cancer therapeutics. Endocrine-Related Cancer (2010) 17 965-975

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Section: Discussionmentioning

confidence: 79%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

Chand¹,

Herridge²,

Thompson³

et al. 2010

Endocrine-Related Cancer

View full text Add to dashboard Cite

show abstract

“…LRH-1 immunoreactivity was detected in adipocytes adjacent to the carcinoma invasion and carcinoma cells, and significant association was detected between LRH-1 and aromatase mRNA levels in the adipose tissues adjacent to the carcinoma [34]. On the other hand, LRH-1 in breast carcinoma cells was not associated with the aromatase expression [35]. Therefore, LRH-1 may mainly regulate aromatase expression in adipose tissue adjacent to the breast carcinoma.…”

Section: Regulation Of Aromatase Expression In Breast Carcinomamentioning

confidence: 99%

Aromatase in Human Breast Carcinoma as a Key Regulator of Intratumoral Sex Steroid Concentrations

et al. 2008

Self Cite

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Abstract. It is well-known that estrogens are closely involved in the growth of human breast carcinomas, and that the great majority of breast carcinoma express estrogen receptors. Recent studies have demonstrated that estrogens are locally produced and act on the breast carcinoma tissue. Among these pathways, aromatase is a key enzyme for intratumoral production of estrogens in breast carcinomas, and aromatase inhibitors are currently used in the breast carcinoma in postmenopausal women as an estrogen deprivation therapy. This review summarizes the results of recent studies on the expression and regulation of aromatase in breast carcinoma tissues, and discusses the potential biological and/or clinical significance of aromatase. Aromatase is abundantly expressed in various cell types, such as carcinoma cells, intratumoral stromal cells, and adipocytes adjacent to the carcinoma, in breast carcinoma tissues. Further, a key regulator for aromatase expression differed according to cell type. In addition, aromatase suppressed in situ production of bioactive androgen, 5α-dihydrotestosterone (DHT), in breast carcinoma. Aromatase inhibitors may thus have additional antiproliferative effects through increasing local DHT concentration with estrogen deprivation.

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“…These effects seem to be mediated by the targeting of genes involved directly in cell proliferation such as CCNE1, CCND1, and MYC (16,17). 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).…”

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

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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.

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Immunolocalization of liver receptor homologue-1 (LRH-1) in human breast carcinoma: Possible regulator of in situ steroidogenesis

Cited by 53 publications

References 38 publications

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

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

Aromatase in Human Breast Carcinoma as a Key Regulator of Intratumoral Sex Steroid Concentrations

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

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