Genes regulated by estrogen in breast tumor cells in vitro are similarly regulated in vivo in tumor xenografts and human breast tumors.
BACKGROUND
Estrogen plays a central role in breast cancer pathogenesis. Although many studies have characterized the estrogen regulation of genes using in vitro cell culture models by global mRNA expression profiling, it is not clear whether these genes are similarly regulated in vivo or how they might be coordinately expressed in primary human tumors.


RESULTS
We generated DNA microarray-based gene expression profiles from three estrogen receptor alpha (ERalpha)-positive breast cancer cell lines stimulated by 17beta-estradiol (E2) in vitro over a time course, as well as from MCF-7 cells grown as xenografts in ovariectomized athymic nude mice with E2 supplementation and after its withdrawal. When the patterns of genes regulated by E2 in vitro were compared to those obtained from xenografts, we found a remarkable overlap (over 40%) of genes regulated by E2 in both contexts. These patterns were compared to those obtained from published clinical data sets. We show that, as a group, E2-regulated genes from our preclinical models were co-expressed with ERalpha in a panel of ERalpha+ breast tumor mRNA profiles, when corrections were made for patient age, as well as with progesterone receptor. Furthermore, the E2-regulated genes were significantly enriched for transcriptional targets of the myc oncogene and were found to be coordinately expressed with Myc in human tumors.


CONCLUSIONS
Our results provide significant validation of a widely used in vitro model of estrogen signaling as being pathologically relevant to breast cancers in vivo.
Creighton
Chad J
CJ
Bioinformatics Program, University of Michigan Medical Center, Ann Arbor, MI 48109, USA.
Cordero
Kevin E
KE
Larios
Jose M
JM
Miller
Rebecca S
RS
Johnson
Michael D
MD
Chinnaiyan
Arul M
AM
Lippman
Marc E
ME
Rae
James M
JM
D000367:Age Factors; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D004958:Estradiol / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011980:Receptors, Progesterone / Q000096:biosynthesis / Q000235:genetics; D015533:Transcriptional Activation; D023041:Xenograft Model Antitumor Assays
D047628:Estrogen Receptor alpha; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D011980:Receptors, Progesterone; D004958:Estradiol