Gene expression profiles in breast tumors regarding the presence or absence of estrogen and progesterone receptors

Abstract

Estrogen acts via its receptor (ER) to stimulate cell growth and differentiation in the mammary gland. ER and progesterone receptor (PR), which is regulated by estrogen via ER, have been used as prognostic markers in clinical management of breast cancer patients. Patients with ER ؊ breast tumors have a poorer prognosis than patients with ER ؉ tumors. The aim of the present study was the identification of tumor-associated genes differentially expressed in breast tumors regarding the presence or absence of ER and PR hybridized with cDNA microarrays containing 4,500 tumorderived expressed sequence tags generated using the ORESTES technique. Samples of human primary breast carcinomas from 38 patients were analyzed. The experiments were performed in triplicates and data from each element were acquired by phosphoimage scanning. Data acquisition was performed using the ArrayVision software. After normalization statistical analysis was applied. In a preliminary analysis, 98 differentially expressed transcripts were identified, 46 were found to be more expressed in ER ؉ /PR ؉ and 52 were found to be more expressed in ER ؊ /PR ؊ breast tumors. Estrogens exert important roles in the development, differentiation and maintenance of several target tissues and are also associated with the development and growth of hormone-dependent tumors such as breast cancer. 1 Most estrogen actions are thought to be mediated through its nuclear estrogen receptors, ER␣ and ER␤, which are members of the nuclear receptors superfamily that are ligand-induced transcription factors. 2 The mechanism by which estrogen receptor (ER) mediates the transactivation of gene expression is complex. 3 Besides the classical ligand-dependent mechanism of ER action in which the hormone-receptor complex regulates gene transcription through its interaction with ERE consensus DNA sequences, the ERs can also regulate gene transcription interacting with other promoter elements such as AP1, 4 SP1 5 and CREs. 6 Thus, estrogen receptors ER␣ and ER␤ can transduce different hormonal signals depending on the ligand and the nature of the hormone-responsive element (HRE). 2 The transactivation elicited by those receptors complexed with E2 may result in opposite signal transduction leading to opposite biologic response in the presence of AP1 and/or CRE sites. 7,8 In addition, several E2-responsive genes are regulated by DNA-independent or -dependent interactions of the ER␣ and SP1 proteins. 9 Alternatively, the signal transduction by growth factors and their tyrosine kinase receptors, such as EGFR, IGFR, erbB-2 and other molecules like cAMP and dopamine, may lead to a ligand-independent ER activation, resulting from the phosphorylation of serine and tyrosine amino acid residues in the AF1 and AF2 domains in the estrogen receptor molecule. 10

Association of theProgesterone ReceptorGene with Breast Cancer Risk: A Single-Nucleotide Polymorphism Tagging Approach

“…The majority of breast cancers stain positively for both PGR and estrogen receptor; receptor positivity is predictive of response to tamoxifen and overall survival. More recently, microarray studies have found PGRnegative tissue to have high levels of transcripts of genes associated with cell proliferation (15).…”

Transcriptional regulation of bidirectional gene pairs by 17-β-estradiol in MCF-7 breast cancer cells

“…In the present study, we employed an integrated computer-assisted and manual search to identify EREs in the promoter region of a set of candidate ER target genes previously identified as being differentially expressed in primary breast tumors based on their estrogen and progesterone status (21). Using this approach, we characterized the promoter region of 83 genes for their potential to be regulated by ER.…”

“…In the present study, we performed an integrated computational and manual search to identify potential ER binding sites in the promoter region of 83 genes previously identified as being differentially expressed in primary breast tumors based on the presence of estrogen and progesterone receptors (21). We identified a subgroup of genes arranged in a head-to-head orientation and separated by a small intergenic region that could be classified as bidirectional promoters.…”

Genomic profiling of breast cancer

“…Patients with ER ( À ) breast tumors have a poorer prognosis than patients with ER ( þ ) tumors [60].The estrogen receptor alpha (ESR1) is a mediator of estrogen response in the breast. The most studied variants in this gene are the PvuII and XbaI polymorphisms, but conversely, they do not play a role in breast cancer risk in Caucasian postmenopausal women [61].…”