Adaptive hypersensitivity to estrogen: mechanism for superiority of aromatase inhibitors over selective estrogen receptor modulators for breast cancer treatment and prevention.

Abstract

Clinical observations suggest that human breast tumors can adapt to endocrine therapy by developing hypersensitivity to estradiol (E 2 ). To understand the mechanisms responsible, we examined estrogenic stimulation of cell proliferation in a model system and provided in vitro and in vivo evidence that long-term E 2 deprivation (LTED) causes 'adaptive hypersensitivity'. The enhanced responses to E 2 do not involve mechanisms acting at the level of transcription of estrogen-regulated genes. We found no evidence of hypersensitivity when examining the effects of E 2 on regulation of c-myc, pS2, progesterone receptor, several estrogen receptor (ER) reporter genes, or c-myb in hypersensitive cells. Estrogen deprivation of breast cells long-term does up-regulate both the MAP kinase and phosphatidyl-inositol 3-kinase pathways. As a potential explanation for up-regulation of these signaling pathways, we found that ERα is 4-to 10-fold up-regulated and co-opts a classic growth factor pathway using Shc, Grb-2 and Sos. This induces rapid non-genomic effects which are enhanced in LTED cells. E 2 binds to cell membrane-associated ERα, physically associates with the adapter protein SHC, and induces its phosphorylation. In turn, Shc binds Grb-2 and Sos, which results in the rapid activation of MAP kinase. These non-genomic effects of E 2 produce biological effects as evidenced by Elk activation and by morphological changes in cell membranes. Further proof of the non-genomic effects of E 2 involved use of cells which selectively expressed ERα in the nucleus, cytosol and cell membrane. We created these COS-1 'designer cells' by transfecting ERα lacking a nuclear localization signal and containing a membrane localizing signal.The concept of 'adaptive hypersensitivity' and the mechanisms responsible for this phenomenon have important clinical implications. Adaptive hypersensitivity would explain the superiority of aromatase inhibitors over the selective ER modulators (SERMs) for treatment of breast cancer. The development of highly potent third-generation aromatase inhibitors allows reduction of breast tissue E 2 to very low levels and circumvents the enhanced sensitivity of these cells to the proliferative effects of E 2 . Clinical trials in the adjuvant, neoadjuvant and advanced disease settings demonstrate the greater clinical efficacy of the aromatase inhibitors over the SERMs. More recent observations indicate that the aromatase inhibitors are superior for the prevention of breast cancer as well. These observations may be explained by the hypothesis that estrogens induce breast cancer both by stimulating cell proliferation and by their metabolism to genotoxic products. The SERMs block ER-mediated proliferation only, whereas the aromatase inhibitors exert dual effects on proliferation and genotoxic metabolite formation.

Quantitative Nanoproteomics for Protein Complexes (QNanoPX) Related to Estrogen Transcriptional Action

“…Estrogen signaling is complex, involving two different isoforms of the estrogen receptor, ␣ (ER␣) 1 and ␤ (ER␤), as well as several different pathways that affect the expression of a number of genes either directly or indirectly. When activated by 17␤-estradiol (E2), the ERs are translocated from the cytosol to the nucleus where the nuclear ERs bind to ERE and recruit other proteins in a complex by promoting, as an activator, or blocking, as a repressor, the recruitment of RNA polymerase to the target genes.…”

“…This process, which is known as the genomic pathway, is significantly involved with many diseases, including various cancers. A nongenomic pathway that involves membrane receptors and protein kinases to send the transduction signals to the nucleus has also been described (1,2). Although there have been studies involving proteomics profiling to identify estrogenresponsive proteins (3,4), the analysis of protein complexes based on a proteomics approach could provide more insights into specific signaling pathways and cross-interactions, which are rarely explored by other approaches.…”

Expression of sex steroid receptor subtypes in normal and malignant breast tissue – a pilot study in postmenopausal women

“…There are observations to suggest that human breast tumors can adapt to endocrine therapy by developing hypersensitivity to estradiol. Long-term estrogen deprivation of breast cells up-regulates both the MAP kinase and phosphatidyl-inositol 3-kinase pathways and during this process ERa is markedly increased [26]. There are also indications that ERß positive tumors are generally of low biological aggressiveness and are likely to respond to hormonal therapy [27].…”

Growth factor-driven mechanisms associated with resistance to estrogen deprivation in breast cancer: new opportunities for therapy

“…HER2 overexpression and its cross-talk with ERa appears to be a common feature of acquired tamoxifen-stimulated MCF-7 and T47D xenograft models (Schafer et al 2003). In parallel, Berstein et al (2003Berstein et al ( , 2004 have demonstrated that long-term tamoxifen treatment of MCF-7 breast cancer cells (LTTT) in a castrated in vivo xenograft model is associated with early adaptive increases in MAP kinase signaling. This event promotes hypersensitivity to the agonistic effects of this anti-hormone and subsequently to estradiol, where the critical role of such signaling is evidenced by marked growth inhibitory effects of a Ras antagonist.…”