Non-genomic actions of estradiol and 4-OH-tamoxifen on murine breast cancer cells

Raffo,Diego; Pontiggia,Osvaldo; Bal de Kier Joffé,Elisa; Simian,Marina

doi:10.3892/or.2014.3558

Non-genomic actions of estradiol and 4-OH-tamoxifen on murine breast cancer cells

Authors:
- Diego Raffo
- Osvaldo Pontiggia
- Elisa Bal de Kier Joffé
- Marina Simian
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Affiliations: Research Area, Institute of Oncology ‘Ángel H. Roffo’, Buenos Aires C1417DTB, Argentina
Published online on: October 22, 2014 https://doi.org/10.3892/or.2014.3558
Pages: 439-447

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Abstract

Estrogens and tamoxifen do not only exert their effects at the genomic level, but also play a role at the cell membrane activating downstream signaling pathways. We recently characterized an estrogen receptor-positive epithelial murine breast cancer cell line, LM05-E. Utilizing this cell line and MCF-7 cells, we compared the non-genomic effects of estradiol and 4-OH-tamoxifen. We showed that, similar to estradiol, tamoxifen activated the MAPK/ERK 1/2 pathway; however, we did not find activation of PI3K/AKT by either estradiol or tamoxifen. Short-term treatments with estradiol stimulated, whereas tamoxifen inhibited cell proliferation. Using pharmacological inhibitors we showed that the effect of estradiol was mediated by the MAPK/ERK 1/2 pathway, but that inhibition of this pathway did not affect tamoxifen. Surprisingly, however, blocking of PI3K/AKT signaling interfered with the inhibitory effect of tamoxifen. Analysis of the involvement of the EGFR support previous findings that designate this receptor as a mediator of the non-genomic effects of estradiol; blocking EGFR also reverses the inhibitory effect of tamoxifen. Finally, matrix metalloproteinases (MMPs) were confirmed to be involved in the proliferative effect of estradiol. These results demonstrated the novel non-genomic effects of tamoxifen and revealed that pathways downstream of EGFR and PI3K/AKT are involved in the inhibition of cell proliferation. Caution should be exercised when analyzing strategies that aim at combining endocrine therapy with specific signaling inhibitors.

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