Classifying the estrogen receptor status of breast cancers by expression profiles reveals a poor prognosis subpopulation exhibiting high expression of the ERBB2 receptor

Abstract

Recent work using expression profiling to computationally predict the estrogen receptor (ER) status of breast tumors has revealed that certain tumors are characterized by a high prediction uncertainty ('low-confidence'). We analyzed these 'low-confidence' tumors and determined that their 'uncertain' prediction status arises as a result of widespread perturbations in multiple genes whose expression is important for ER subtype discrimination. Patients with 'low-confidence' ER+ tumors exhibited a significantly worse overall survival (P=0.03) and shorter time to distant metastasis (P=0.004) compared with their 'high-confidence' ER+ counterparts, indicating that the 'high-' and 'low-confidence' binary distinction is clinically meaningful. We then discovered that elevated expression of the ERBB2 receptor is significantly correlated with a breast tumor exhibiting a 'low-confidence' prediction, and this association was subsequently validated across multiple independently derived breast cancer expression datasets employing a variety of different array technologies and patient populations. Although ERBB2 signaling has been proposed to inhibit the transcriptional activity of ER, a large proportion of the perturbed genes in the 'low-confidence'/ERBB2+ samples are not known to be estrogen responsive, and a recently described bioinformatic algorithm (DEREF) was used to demonstrate the absence of potential estrogen-response elements (EREs) in their promoters. We propose that a significant portion of ERBB2's effects on ER+ breast tumors may involve ER-independent mechanisms of gene activation, which may contribute to the clinically aggressive behavior of the 'low-confidence' breast tumor subtype.

Endonuclease G promotes cell death of non-invasive human breast cancer cells

“…These markers are frequently used in breast cancer studies to determine the degree of differentiation and the invasiveness potential of breast cancer cells [45,46]. An inverse relationship between invasiveness and ER immunoreactivity is usually observed by immunohistochemistry or molecular biology methods [47,48]. Expression of vimentin alone or its co-expression with keratin or tenascin-C was described to be strongly associated with an increased invasive behavior of breast cancer [49][50][51].…”

Evidence for Selective Expression of the p53 Codon 72 Polymorphs: Implications in Cancer Development

“…Peripheral blood was obtained from a total of 160 Chinese (11) and 105 Polish healthy subjects. Ninety-four Chinese breast cancer samples and histologically matched normal tissues, which have been used in our previous study (12), were obtained from the National Cancer Center tissue repository on written approval from the repository management and ethics committee. DNA and mRNA were prepared according to standard procedures using commercial kits.…”

“…We also evaluated the p53 expression status in the corresponding adjacent histologically normal tissues of some of the heterozygote cancers, which were of the luminal type (12). This analysis again revealed that the arg allele was preferentially expressed in the histologically normal tissues (either arg alone or arg and pro) and there was no preferential expression of the pro allele (representative data shown in Fig.…”

“…The frequency of mutation at codon 80 was 25% of the arg-expressing tumors. (12) Table 2). However, the numbers were not statistically significant due to the small population size.…”

Immediate Gene Expression Changes After the First Course of Neoadjuvant Chemotherapy in Patients with Primary Breast Cancer Disease

“…From the theoretical point of view, it is unexpected that the therapeutic response in patients with breast cancer might be independent from the ER/PgR status. It is more probable that the prognostic impact of receptors' expression depends on the impact of other variables, e.g., the impact of the ERBB2 receptor (7,8). When conventional biological techniques are used, finding such factors is problematical because all of these techniques survey one gene at a time.…”