The pattern of ERα expression in normal breast tissue compared with precancerous and cancerous lesions is strikingly different. In normal breast tissue, ERα expression is restricted to a small proportion of non-proliferating luminal epithelial cells, typically at low to intermediate levels [8
]. However, in more than half of premalignant lesions and carcinomas, this dissociation breaks down and the receptor is detected in proliferating cells, generally at higher levels [8
]. Additionally, there is a striking increase in the intracellular amount of ERα protein [10
]. A significant unknown in the field of breast cancer is what drives the change in ERα expression and distribution in breast lesions. Holst et al.
] used fluorescence in situ
hybridization (FISH) to probe a tissue microarray containing 2,222 invasive breast cancers and 295 normal, pre-malignant, and pre-invasive samples and found ESR1
gene amplification in 358 samples (21%) of the 1,739 invasive breast carcinomas with analyzable FISH data. Virtually all (99%) cases with amplification exhibited correspondingly high ERα protein levels as measured by immunohistochemistry. Characterization of the ESR1
amplicon at 6q25.1 by PCR-based methods found that it was relatively small and did not extend into any other genes. Furthermore, ESR2
, which encodes a second ER, ERβ, was not amplified. Amplification of other known oncogenes (HER2/neu
) was detected in invasive cancer samples, although these were found to be independent of ESR1
amplification. Interestingly, ESR1
amplification was observed in proliferative benign breast lesions (36.4% of papillomas and 8.3% of usual ductal hyperplasia) and carcinomas in situ
(35% ductal and 33% lobular) in addition to more advanced tumors [4
]. While these studies require independent validation, the data provide evidence that amplification of ERα appears in early lesions and may contribute, in part, to the appearance of high levels of ERα in breast tumorigenesis.
Gene amplification alone, however, cannot explain all cases involving high ERα protein levels. Only 54% of cancers with high ERα expression also had gene amplification [4
]. The remaining 46% showed high ERα expression without gene amplification [4
]. This suggests that other mechanisms contribute to high ERα protein levels, such as altered regulation of ESR1
transcription, mRNA stability, or ERα protein turnover. For example, recent studies have demonstrated that disruption of caveolin-1 and micro-ribonucleic acid 206 can increase ERα levels [11
]. How such upstream factors regulate the ERα gene and protein is not well understood and needs further attention.