The relationships between snail1 and estrogen receptor signaling in breast cancer cells.
The loss of hormonal dependency of breast tumor cells is often accompanied with the appearance of epithelial-mesenchymal transition (EMT) features and increase in cell metastasis and invasiveness. The central role in the EMT belongs to transcription factors Snail responded for the decrease in E-cadherin expression and cell contacts, stimulation of cell mobility and invasiveness. Aim was to study the relationships between estrogen receptor machinery and Snail1 signaling, and mechanism of Snail1 regulation in hormone-resistant breast cancer cells. The experiments were performed on the estrogen-dependent MCF-7 breast cancer cells, estrogen-hyposensitive MCF-7/LS subline generated through long-term cultivation of the parental cells in steroid-free medium, and ER-negative estrogen-resistant HBL-100 cells. Snail1, estrogen receptor, p65 NF-κB, E-cadherin levels were analyzed by Western blot. We found that decrease in the estrogen dependency is correlated with increase in Snail1 expression and activity, we demonstrated the Snail1 involvement in the negative regulation of ER, and showed that Snail1 inhibition partially restores the sensitivity of the estrogen-hyposensitive cells to antiestrogen tamoxifen. Furthermore, NF-κB was found to serve as a positive regulator of Snail1 in breast cancer cells, and simultaneous inhibition of NF-κB and Snail1 resulted in additional increase in cell response to tamoxifen. In general, the results obtained demonstrate the phenomenon of Snail1 activation in the hormone-resistant breast cancer cells, and show that Snail1 and NF-κB may serve as an important targets in the treatment of breast cancer, both estrogen-dependent and estrogen-independent tumors.
Laboratory of Clinical Biochemistry, Institute of Clinical Oncology, N.N. Blokhin Cancer Research Centre, Kashirskoye sh. 24, Moscow 115478, Russia. alex.scherbakov@gmail.com
Alexander M
AM
Scherbakov
Olga E
OE
Andreeva
Valentina A
VA
Shatskaya
Mikhail A
MA
Krasil'nikov
D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D017209:Apoptosis; D001943:Breast Neoplasms / Q000378:metabolism*; D015820:Cadherins / Q000096:biosynthesis; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D006801:Humans; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D011960:Receptors, Estrogen / Q000378:metabolism*; D015398:Signal Transduction; D000071250:Snail Family Transcription Factors; D013629:Tamoxifen / Q000494:pharmacology; D051996:Transcription Factor RelA / Q000096:biosynthesis; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D018931:Antineoplastic Agents, Hormonal; D015820:Cadherins; D016328:NF-kappa B; D034741:RNA, Small Interfering; D011960:Receptors, Estrogen; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; D051996:Transcription Factor RelA; D014157:Transcription Factors; D013629:Tamoxifen