LRH-1 expression patterns in breast cancer tissues are associated with tumour aggressiveness

Jia-Min B Pang; Ramyar Molania; Ashwini Chand; Kevin Knower; Elena A Takano; David J Byrne; Thomas Mikeska; Ewan K A Millar; Cheok Soon Lee; Sandra A O'Toole; Colin Clyne; Kylie L Gorringe; Alexander Dobrovic; Stephen B Fox

doi:10.18632/oncotarget.18886

LRH-1 expression patterns in breast cancer tissues are associated with tumour aggressiveness

Oncotarget. 2017 Jul 28;8(48):83626-83636. doi: 10.18632/oncotarget.18886. eCollection 2017 Oct 13.

Authors

Jia-Min B Pang¹, Ramyar Molania^{2

3}, Ashwini Chand⁴, Kevin Knower⁴, Elena A Takano¹, David J Byrne¹, Thomas Mikeska^{2

5

6}, Ewan K A Millar^{7

8

9

10}, Cheok Soon Lee^{10

11

12}, Sandra A O'Toole^{7

11

13}, Colin Clyne⁴, Kylie L Gorringe^{6

14

15}, Alexander Dobrovic^{2

5

6}, Stephen B Fox^{1

6

15}

Affiliations

¹ Department of Pathology, Peter MacCallum Cancer Centre, Victorian Comprehensive Cancer Centre, Melbourne, VIC 3000, Australia.
² Translational Genomics & Epigenomics Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, VIC 3084, Australia.
³ Department of Medicine, University of Melbourne, Parkville, VIC 3010, Australia.
⁴ Cancer Drug Discovery Laboratory, Hudson Institute of Medical Research, Clayton, VIC 3168, Australia.
⁵ School of Cancer Medicine, La Trobe University, Bundoora, VIC 3084, Australia.
⁶ Department of Pathology, University of Melbourne, Parkville, VIC 3010, Australia.
⁷ The Kinghorn Cancer Centre and Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia.
⁸ Department of Anatomical Pathology, South Eastern Area Pathology Service, St George Hospital, Kogarah, NSW 2217, Australia.
⁹ School of Medical Sciences, University of New South Wales, Kensington, NSW 2052, Australia.
¹⁰ Discipline of Pathology, School of Medicine, University of Western Sydney, Campbelltown, NSW 2751, Australia.
¹¹ Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, NSW 2005, Australia.
¹² Cancer Pathology, Bosch Institute, University of Sydney, NSW 2006, Australia.
¹³ Sydney Medical School, University of Sydney, NSW 2006, Australia.
¹⁴ Cancer Genomics Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia.
¹⁵ Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC 3010, Australia.

Abstract

The significance and regulation of liver receptor homologue 1 (LRH-1, NR5A2), a tumour-promoting transcription factor in breast cancer cell lines, is unknown in clinical breast cancers. This study aims to determine LRH-1/NR5A2 expression in breast cancers and relationship with DNA methylation and tumour characteristics. In The Cancer Genome Atlas breast cancer cohort NR5A2 expression was positively associated with intragenic CpG island methylation (1.4-fold expression for fully methylated versus not fully methylated, p=0.01) and inversely associated with promoter CpG island methylation (0.6-fold expression for fully methylated versus not fully methylated, p=0.036). LRH-1 immunohistochemistry of 329 invasive carcinomas and ductal carcinoma in situ (DCIS) was performed. Densely punctate/coarsely granular nuclear reactivity was significantly associated with high tumour grade (p<0.005, p=0.033 in invasive carcinomas and DCIS respectively), negative estrogen receptor status (p=0.008, p=0.038 in overall cohort and invasive carcinomas, respectively), negative progesterone receptor status (p=0.003, p=0.013 in overall cohort and invasive carcinomas, respectively), HER2 amplification (overall cohort p=0.034) and non-luminal intrinsic subtype (p=0.018, p=0.038 in overall cohort and invasive carcinomas, respectively). These significant associations of LRH-1 protein expression with tumour phenotype suggest that LRH-1 is an important indicator of tumour biology in breast cancers and may be useful in risk stratification.

Keywords: DNA methylation; NR5A2; breast carcinoma; estrogen signalling; immunohistochemistry.