Mechanism of estrogen-induced apoptosis in breast cancer cells: Role of the NF-κB signaling pathway

Abstract

The ability of sex steroid hormones to up-regulate the apoptotic signaling proteins is well documented; however, the apoptotic potential of sex hormones is not remarkable and fully compensated by their growth stimulatory action to target cells. In the present study using the long-term cultivation of estrogen-dependent MCF-7 breast cancer cells in steroid-free medium, we have established a cell subline, designed as MCF-7/LS, which was characterized by the resistance to growth stimulatory estradiol action and hypersensitivity to estrogen-induced apoptosis. We have demonstrated that estrogen treatment of the cells does not influence on the level of TNF-R1 or Fas, but dramatically decreases the transcriptional activity of NF-kappaB. Importantly, the MCF-7/LS cells, which are insensitive to growth stimulatory estrogen action, retain the ability to decrease in the NF-kappaB activity in response to estrogen stimulus. Furthermore, the significant increase in the basal (in the absence of ligand) estrogen receptor (ER)-dependent transcriptional activity in the MCF-7/LS cells was revealed and reciprocal transcriptional antagonism between ER and NF-kappaB was demonstrated. Finally, we proved the possible involvement of phosphatidylinositol-3 kinase (PI3K) in the ligand-independent ER activation. In general, the results presented suggest that long-term growth of MCF-7 breast cancer cells in steroid-free medium is accompanied with the increase in the basal ER-dependent transcriptional activity as well as the maintenance of the negative regulatory loop ER-NF-kappaB. The latter may be considered as one of the factors resulting in a disbalance between pro- and anti-apoptotic pathways and enhancement in estrogen apoptotic action in the cells.

The Expression and DNA-Binding Activity of NF-κB Nuclear Transcription Factor in the Tumors of Patients with Breast Cancer

“…The significance of this factor is particularly high in estrogen receptor (ER)-negative breast tumors carrying epidermal growth factor or HER-2/neu receptors [5]. Hyperactivation of NF-κB is a cause of BC resistance to antiestrogens, drugs, and radiotherapy [2,3,8,10,13]. According to some data, evaluation of NF-κB activation in ER-positive BC helps to detect a subgroup of hormone-resistant patients [14,15].…”

Classification and Analysis of Regulatory Pathways Using Graph Property, Biochemical and Physicochemical Property, and Functional Property

“…The relationship between “Metabolism” pathways and GO term “GO:0043627 response to estrogen stimulus” may be indirect. Estrogen can introduce dramatic changes of cell, such as apoptosis and carcinogenesis [92], [93]. During these cellular changes, the metabolism pathways will change as well.…”

Consequences of nongenomic actions of estradiol on pathogenic genital tract response

“…The decreased transcriptional activity of the NF-kb signaling pathway is another previously reported estradiol effect [35]. Though this modification could alter the inflammatory response via a genomic pathway, the decreased activity of this transcription factor is mediated by the nongenomic pathway of estradiol.…”