Genes that co-cluster with estrogen receptor alpha in microarray analysis of breast biopsies

Abstract

The estrogen receptor plays a critical role in the pathogenesis and clinical behavior of breast cancer. To better understand the molecular basis of estrogen-dependent forms of this disease we studied gene expression profiles from 53 primary breast cancer biopsies. Gene expression data for more than 7000 genes were generated from each tumor sample with oligo microarrays. A standard correlation-clustering algorithm identified 18 genes that co-clustered with estrogen receptor alpha. Eleven of these genes had previously been associated with estrogen regulation or breast tumorigenesis including trefoil factor 1 and estrogen regulated LIV-1. Additional study of these 18 genes may further delineate the role of estrogen receptor in breast cancer, generate new predictive biomarkers for response to endocrine therapies and identify novel therapeutic targets. The Pharmacogenomics Journal ( BACKGROUNDThe estrogen receptor is a ligand-activated transcription factor containing hormone binding, DNA binding and transcription activation domains. 1 It is expressed in normal breast and 50-80% of breast cancers, depending on the assay used. 2-4 Estrogen receptor (ER) is a favorable prognostic factor and ER positive malignancies have a lower risk of relapse and a better overall survival. 5 However, ESR1 analysis is most useful in predicting response to endocrine therapies, although approximately half of all ER-positive cancers do not respond to antiestrogens or estrogen deprivation therapies. 6 The molecular basis for ESR1-positive, endocrine therapy-resistant disease is not well understood. Somatic mutations in ESR1 are rare, even in breast cancers that have acquired resistances to endocrine therapies. This finding has focused attention on other mechanisms, including the overexpression of tyrosone-kinase linked growth factor receptors, transcriptional coactivators such as AIB1 (amplified in breast cancer 1) or cell cycle regulators including Cyclin D1. Additional possibilities include mutations in other genes involved in the regulation of estrogen-dependent growth.Expression of the estrogen-regulated genes, progesterone receptor (PGR) and trefoil factor 1 (TFF1 or PS2) indicate the presence of a functional and activated ER. 7 Both of these proteins are predictive biomarkers for breast cancer endocrine therapy, although less valuable than ER in distinguishing estrogen-dependent from estrogen-independent breast cancer. The use of PGR improves upon the predictive value of ER alone, yet ෂ 40% of tumors that express both ER and PGR fail to respond to endocrine treatments in the metastatic setting. 8 Similarly, TFF1 is associated with a good prognosis and predicts a positive response to hormonal therapy, but it has not proved to be sufficient as a predictive biomarker for routine evaluation of breast cancer. 9 Thus, PGR and TFF1 may be modestly useful

Squalene epoxidase, located on chromosome 8q24.1, is upregulated in 8q+ breast cancer and indicates poor clinical outcome in stage I and II disease

“…No significant differences between the subgroups expressing SQLE mRNA above and below the median were revealed. On the other hand, LIV-1 mRNA expression level was weakly positively correlated to ER status (Po0.05) as already reported from other studies (Dressman et al, 2001), thereby confirming the validity of our sample panel.…”

Gene expression profiling of cancer progression reveals intrinsic regulation of transforming growth factor-β signaling in ErbB2/Neu-induced tumors from transgenic mice

“…Several of the 82 genes (Etv1, Eif4ebp1, Ghr, Id2, Kai1, Tpd52) that were progressively altered during ErbB2/Neu-induced tumorigenesis are already known to be associated with human breast cancer, highlighting the relevance of this model in evaluating alterations of the transcriptome that are associated with progression of tumorigenesis. Interestingly in previous studies, there were only a small number of genes that were common to all of the human breast tumor expression profiling experiments that identified ErbB2/Neu tumor molecular signatures, and these genes are contained in the ErbB2/Neu amplicon (Perou et al, 2000;Kauraniemi et al, 2001;Wilson et al, 2002;Dressman et al, 2003;Bertucci et al, 2004). The analytical approaches and perhaps the heterogeneity of human ErbB2/Neu-positive breast tumors in these experiments seem to preclude identification of universal downstream targets of ErbB2/Neu signaling.…”

“…Further characterization of these genes should provide insight into the tumorigenic events associated with ErbB2/Neu overexpression and thus a more complete understanding of the underlying biological mechanisms of the ErbB2/Neu tumorigenic cascade. Owing to the importance of ErbB2/Neu overexpression in human breast cancers, several groups have previously used expression profiling to identify genes associated with ErbB2/Neu expression in breast tumors and cell lines (Perou et al, 2000;Kauraniemi et al, 2001Kauraniemi et al, , 2004Desai et al, 2002;Wilson et al, 2002;Andrechek et al, 2003;Dressman et al, 2003;Kumar-Sinha et al, 2003;Mackay et al, 2003;Bertucci et al, 2004). Importantly, none have examined the expression profiles of preneoplastic tissue to identify alterations of gene expression that are associated with tumor progression in an in vivo model.…”

Identification and validation of an ERBB2 gene expression signature in breast cancers

“…In the study of Wilson et al (2002) using a microarray with B5.000 cDNAs, only few genes from 17q were among those upregulated genes; these included RPL19 and LASP1. Dressman et al (2003) studied 34 tumours and established a gene expression signature specific of ERBB2 þ samples that contained several 17q genes including GRB7, NR1D1, PSMB3 and RPL19. Sorlie et al (2003) have also defined ERBB2 þ signature with five genes from 17q12, including ERBB2, GRB7 and PPARBP.…”