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.