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Estrogen receptor beta growth-inhibitory effects are repressed through activation of MAPK and PI3K signalling in mammary epithelial and breast cancer cells.
Oncogene. 2013 May 09; 32(19):2390-402.O

Abstract

Two thirds of breast cancers express estrogen receptors (ER). ER alpha (ERα) mediates breast cancer cell proliferation, and expression of ERα is the standard choice to indicate adjuvant endocrine therapy. ERbeta (ERβ) inhibits growth in vitro; its effects in vivo have been incompletely investigated and its role in breast cancer and potential as alternative target in endocrine therapy needs further study. In this work, mammary epithelial (EpH4 and HC11) and breast cancer (MC4-L2) cells with endogenous ERα and ERβ expression and T47-D human breast cancer cells with recombinant ERβ (T47-DERβ) were used to explore effects exerted in vitro and in vivo by the ERβ agonists 2,3-bis (4-hydroxy-phenyl)-propionitrile (DPN) and 7-bromo-2-(4-hydroxyphenyl)-1,3-benzoxazol-5-ol (WAY). In vivo, ERβ agonists induced mammary gland hyperplasia and MC4-L2 tumour growth to a similar extent as the ERα agonist 4,4',4''-(4-propyl-(1H)-pyrazole-1,3,5-triyl) trisphenol (PPT) or 17β-estradiol (E2) and correlated with higher number of mitotic and lower number of apoptotic features. In vitro, in MC4-L2, EpH4 or HC11 cells incubated under basal conditions, ERβ agonists induced apoptosis measured as upregulation of p53 and apoptosis-inducible factor protein levels and increased caspase 3 activity, whereas PPT and E2 stimulated proliferation. However, when extracellular signal-regulated kinase 1 and 2 (ERK ½) were activated by co-incubation with basement membrane extract or epidermal growth factor, induction of apoptosis by ERβ agonists was repressed and DPN induced proliferation in a similar way as E2 or PPT. In a context of active ERK ½, phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/RAC-alpha serine/threonine-protein kinase (AKT) signalling was necessary to allow proliferation stimulated by ER agonists. Inhibition of MEK ½ with UO126 completely restored ERβ growth-inhibitory effects, whereas inhibition of PI3K by LY294002 inhibited ERβ-induced proliferation. These results show that the cellular context modulates ERβ growth-inhibitory effects and should be taken into consideration upon assessment of ERβ as target for endocrine treatment.

Authors+Show Affiliations

Department of Chemistry, Universidade de Aveiro, Campus Universitario de Santigo, Aveiro, Portugal.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22751110

Citation

Cotrim, C Z., et al. "Estrogen Receptor Beta Growth-inhibitory Effects Are Repressed Through Activation of MAPK and PI3K Signalling in Mammary Epithelial and Breast Cancer Cells." Oncogene, vol. 32, no. 19, 2013, pp. 2390-402.
Cotrim CZ, Fabris V, Doria ML, et al. Estrogen receptor beta growth-inhibitory effects are repressed through activation of MAPK and PI3K signalling in mammary epithelial and breast cancer cells. Oncogene. 2013;32(19):2390-402.
Cotrim, C. Z., Fabris, V., Doria, M. L., Lindberg, K., Gustafsson, J. Å., Amado, F., Lanari, C., & Helguero, L. A. (2013). Estrogen receptor beta growth-inhibitory effects are repressed through activation of MAPK and PI3K signalling in mammary epithelial and breast cancer cells. Oncogene, 32(19), 2390-402. https://doi.org/10.1038/onc.2012.261
Cotrim CZ, et al. Estrogen Receptor Beta Growth-inhibitory Effects Are Repressed Through Activation of MAPK and PI3K Signalling in Mammary Epithelial and Breast Cancer Cells. Oncogene. 2013 May 9;32(19):2390-402. PubMed PMID: 22751110.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Estrogen receptor beta growth-inhibitory effects are repressed through activation of MAPK and PI3K signalling in mammary epithelial and breast cancer cells. AU - Cotrim,C Z, AU - Fabris,V, AU - Doria,M L, AU - Lindberg,K, AU - Gustafsson,J-Å, AU - Amado,F, AU - Lanari,C, AU - Helguero,L A, Y1 - 2012/07/02/ PY - 2012/7/4/entrez PY - 2012/7/4/pubmed PY - 2013/10/31/medline SP - 2390 EP - 402 JF - Oncogene JO - Oncogene VL - 32 IS - 19 N2 - Two thirds of breast cancers express estrogen receptors (ER). ER alpha (ERα) mediates breast cancer cell proliferation, and expression of ERα is the standard choice to indicate adjuvant endocrine therapy. ERbeta (ERβ) inhibits growth in vitro; its effects in vivo have been incompletely investigated and its role in breast cancer and potential as alternative target in endocrine therapy needs further study. In this work, mammary epithelial (EpH4 and HC11) and breast cancer (MC4-L2) cells with endogenous ERα and ERβ expression and T47-D human breast cancer cells with recombinant ERβ (T47-DERβ) were used to explore effects exerted in vitro and in vivo by the ERβ agonists 2,3-bis (4-hydroxy-phenyl)-propionitrile (DPN) and 7-bromo-2-(4-hydroxyphenyl)-1,3-benzoxazol-5-ol (WAY). In vivo, ERβ agonists induced mammary gland hyperplasia and MC4-L2 tumour growth to a similar extent as the ERα agonist 4,4',4''-(4-propyl-(1H)-pyrazole-1,3,5-triyl) trisphenol (PPT) or 17β-estradiol (E2) and correlated with higher number of mitotic and lower number of apoptotic features. In vitro, in MC4-L2, EpH4 or HC11 cells incubated under basal conditions, ERβ agonists induced apoptosis measured as upregulation of p53 and apoptosis-inducible factor protein levels and increased caspase 3 activity, whereas PPT and E2 stimulated proliferation. However, when extracellular signal-regulated kinase 1 and 2 (ERK ½) were activated by co-incubation with basement membrane extract or epidermal growth factor, induction of apoptosis by ERβ agonists was repressed and DPN induced proliferation in a similar way as E2 or PPT. In a context of active ERK ½, phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/RAC-alpha serine/threonine-protein kinase (AKT) signalling was necessary to allow proliferation stimulated by ER agonists. Inhibition of MEK ½ with UO126 completely restored ERβ growth-inhibitory effects, whereas inhibition of PI3K by LY294002 inhibited ERβ-induced proliferation. These results show that the cellular context modulates ERβ growth-inhibitory effects and should be taken into consideration upon assessment of ERβ as target for endocrine treatment. SN - 1476-5594 UR - https://www.unboundmedicine.com/medline/citation/22751110/Estrogen_receptor_beta_growth_inhibitory_effects_are_repressed_through_activation_of_MAPK_and_PI3K_signalling_in_mammary_epithelial_and_breast_cancer_cells_ L2 - https://doi.org/10.1038/onc.2012.261 DB - PRIME DP - Unbound Medicine ER -