The estrogen and c-Myc target gene HSPC111 is over-expressed in breast cancer and associated with poor patient outcome.
BACKGROUND
Estrogens play a pivotal role in the initiation and progression of breast cancer. The genes that mediate these processes are not fully defined, but potentially include the known mammary oncogene MYC. Characterization of estrogen-target genes may help to elucidate further the mechanisms of estrogen-induced mitogenesis and endocrine resistance.


METHODS
We used a transcript profiling approach to identify targets of estrogen and c-Myc in breast cancer cells. One previously uncharacterized gene, namely HBV pre-S2 trans-regulated protein 3 (HSPC111), was acutely upregulated after estrogen treatment or inducible expression of c-Myc, and was selected for further functional analysis using over-expression and knock-down strategies. HSPC111 expression was also analyzed in relation to MYC expression and outcome in primary breast carcinomas and published gene expression datasets.


RESULTS
Pretreatment of cells with c-Myc small interfering RNA abrogated estrogen induction of HSPC111, identifying HSPC111 as a potential c-Myc target gene. This was confirmed by the demonstration of two functional E-box motifs upstream of the transcription start site. HSPC111 mRNA and protein were over-expressed in breast cancer cell lines and primary breast carcinomas, and this was positively correlated with MYC mRNA levels. HSPC111 is present in a large, RNA-dependent nucleolar complex, suggesting a possible role in ribosomal biosynthesis. Neither over-expression or small interfering RNA knock-down of HSPC111 affected cell proliferation rates or sensitivity to estrogen/antiestrogen treatment. However, high expression of HSPC111 mRNA was associated with adverse patient outcome in published gene expression datasets.


CONCLUSIONS
These data identify HSPC111 as an estrogen and c-Myc target gene that is over-expressed in breast cancer and is associated with an adverse patient outcome.
Butt
Alison J
AJ
Cancer Research Program, Garvan Institute of Medical Research, St, Vincent's Hospital, Victoria Street, Darlinghurst, New South Wales 2010, Australia.
Sergio
C Marcelo
CM
Inman
Claire K
CK
Anderson
Luke R
LR
McNeil
Catriona M
CM
Russell
Amanda J
AJ
Nousch
Marco
M
Preiss
Thomas
T
Biankin
Andrew V
AV
Sutherland
Robert L
RL
Musgrove
Elizabeth A
EA
D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality / Q000628:therapy; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D024202:Electrophoretic Mobility Shift Assay; D004967:Estrogens / Q000235:genetics*; D005260:Female; D005455:Fluorescent Antibody Technique; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D016259:Genes, myc; D006514:Hepatitis B Surface Antigens / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D016196:S Phase; D016019:Survival Analysis; D015854:Up-Regulation
D004967:Estrogens; D006514:Hepatitis B Surface Antigens; C530131:NOP16 protein, human; D011498:Protein Precursors; D011506:Proteins; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C050807:presurface protein 2, hepatitis B surface antigen