LSD1 overexpression is associated with poor prognosis in basal-like breast cancer, and sensitivity to PARP inhibition.

Satoi Nagasawa,Anand D Jeyasekharan,Marta Roche-Molina,Yuko Nakagawa,Koichiro Tsugawa,Ana J Narváez,Ko Sato,Manabu Kubota,Shigeko Ohnuma,Anna S Sedukhina,Juan A Bernal,Ichiro Maeda,Tomohiko Ohta,Jindan Yu

doi:10.1371/journal.pone.0118002

Abstract

LSD1, a lysine-specific histone demethylase, is overexpressed in several types of cancers and linked to poor outcomes. In breast cancer, the significance of LSD1 overexpression is not clear. We have performed an in silico analysis to assess the relationship of LSD1 expression to clinical outcome. We demonstrate that LSD1 overexpression is a poor prognostic factor in breast cancer, especially in basal-like breast cancer, a subtype of breast cancer with aggressive clinical features. This link is also observed in samples of triple negative breast cancer. Interestingly, we note that overexpression of LSD1 correlates with down-regulation of BRCA1 in triple negative breast cancer. This phenomenon is also observed in in vitro models of basal-like breast cancer, and is associated with an increased sensitivity to PARP inhibitors. We propose therefore that high expression levels of the demethylase LSD1 is a potential prognostic factor of poor outcome in basal-like breast cancer, and that PARP inhibition may be a therapeutic strategy of interest in this poor prognostic subtype with overexpression of LSD1.

Highlights

LSD1, lysine specific demethylase 1, removes methyl groups from lysine residues of histone H3, thereby regulating gene expression [1]
It is known that LSD1 is overexpressed in Estrogen Receptor (ER)-negative breast cancer, upregulation of LSD1 transcripts is not seen in HER2 type breast cancer that is ER-negative (Fig. 1) [11]
The analysis indicates that cancer with high LSD1 transcripts shows a trend to shorter recurrence free survival (RFS) in basal-like breast cancer with a hazard ratio (HR) of 4.314 (Fig. 2B)

Summary

Introduction

LSD1, lysine specific demethylase 1, removes methyl groups from lysine residues of histone H3, thereby regulating gene expression [1]. LSD1 removes mono- and dimethyl groups from lysine 4 of histone H3 (H3K4) [1]. LSD1 works with androgen/estrogen receptor to remove mono- and dimethyl groups from lysine 9 of histone H3 (H3K9) [2,3]. The control of gene expression by LSD1 has been shown to be vital to multiple processes including organogenesis and stem cell differentiation [4],[5]. PLOS ONE | DOI:10.1371/journal.pone.0118002 February 13, 2015

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