AKT3 regulates ErbB2, ErbB3 and estrogen receptor α expression and contributes to endocrine therapy resistance of ErbB2(+) breast tumor cells from Balb-neuT mice

Nicole Grabinski; Katharina Möllmann; Karin Milde-Langosch; Volkmar Müller; Udo Schumacher; Burkhard Brandt; Klaus Pantel; Manfred Jücker

doi:10.1016/j.cellsig.2014.01.018

AKT3 regulates ErbB2, ErbB3 and estrogen receptor α expression and contributes to endocrine therapy resistance of ErbB2(+) breast tumor cells from Balb-neuT mice

Standard

AKT3 regulates ErbB2, ErbB3 and estrogen receptor α expression and contributes to endocrine therapy resistance of ErbB2(+) breast tumor cells from Balb-neuT mice. / Grabinski, Nicole; Möllmann, Katharina; Milde-Langosch, Karin; Müller, Volkmar ; Schumacher, Udo; Brandt, Burkhard; Pantel, Klaus ; Jücker, Manfred.

In: CELL SIGNAL, Vol. 26, No. 5, 01.05.2014, p. 1021-9.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Grabinski, N, Möllmann, K, Milde-Langosch, K, Müller, V , Schumacher, U, Brandt, B, Pantel, K & Jücker, M 2014, 'AKT3 regulates ErbB2, ErbB3 and estrogen receptor α expression and contributes to endocrine therapy resistance of ErbB2(+) breast tumor cells from Balb-neuT mice', CELL SIGNAL, vol. 26, no. 5, pp. 1021-9. https://doi.org/10.1016/j.cellsig.2014.01.018

APA

Grabinski, N., Möllmann, K., Milde-Langosch, K., Müller, V., Schumacher, U., Brandt, B., Pantel, K., & Jücker, M. (2014). AKT3 regulates ErbB2, ErbB3 and estrogen receptor α expression and contributes to endocrine therapy resistance of ErbB2(+) breast tumor cells from Balb-neuT mice. CELL SIGNAL, 26(5), 1021-9. https://doi.org/10.1016/j.cellsig.2014.01.018

Vancouver

Grabinski N, Möllmann K, Milde-Langosch K, Müller V , Schumacher U, Brandt B et al. AKT3 regulates ErbB2, ErbB3 and estrogen receptor α expression and contributes to endocrine therapy resistance of ErbB2(+) breast tumor cells from Balb-neuT mice. CELL SIGNAL. 2014 May 1;26(5):1021-9. https://doi.org/10.1016/j.cellsig.2014.01.018

Bibtex

@article{91ed8fdc55684c3aa137c5391a8ce536,

title = "AKT3 regulates ErbB2, ErbB3 and estrogen receptor α expression and contributes to endocrine therapy resistance of ErbB2(+) breast tumor cells from Balb-neuT mice",

abstract = "ErbB2(+) breast cancer is an aggressive breast cancer subtype generally associated with lower estrogen receptor alpha (ERα) expression and more aggressive tumor behavior compared to ERα(+)/ErbB2(-) breast cancer. The ErbB2(+) phenotype is associated with resistance to endocrine therapy, e.g. the selective estrogen receptor modulator Tamoxifen. However, the mechanisms underlying endocrine resistance are not fully understood. Here, we investigated the impact of AKT signaling and distinct functional roles of AKT isoforms in ErbB2(+) breast cancer from Balb-neuT mice. AKT isoform specific in vitro kinase assays revealed that AKT3 is activated in Balb-neuT breast tumors in comparison to normal murine breast tissue. Knock-down of AKT3, but not of AKT1 or AKT2, led to reduced expression and tyrosine-phosphorylation of ErbB2 and ErbB3 in Balb-neuT-derived mammary tumor cells. In contrast, expression of ERα was strongly up-regulated and phosphorylation of the AKT substrate Foxo3a which regulates ERα transcription was decreased in AKT3 knockdown cells. These data suggest that ERα expression is down regulated via AKT3/Foxo3a signaling in ErbB2(+) breast cancer cells. Furthermore, up-regulation of ERα after depletion of AKT3 resulted in a significant increase in Tamoxifen responsiveness of Balb-neuT-derived mammary tumor cells. In addition, Tamoxifen resistant human breast cancer cell lines showed increased AKT3 expression and activity in comparison to Tamoxifen responsive MCF-7 cells. Finally, by AKT isoform specific in vitro kinase assays of human breast cancer samples, AKT3 activity was detected in ErbB2(+) and triple negative tumors but not in ERα(+) breast cancer. Our data indicate that AKT3 regulates the expression of ErbB2, ErbB3 and ERα and demonstrate that down-regulation of activated AKT3 can sensitize ErbB2(+) breast cancer cells for treatment with Tamoxifen. Therefore, AKT3 targeting might be a new promising strategy for therapy of ErbB2(+)/ERα(-) breast cancer and might further increase the responsiveness to an endocrine therapy approach.",

author = "Nicole Grabinski and Katharina M{\"o}llmann and Karin Milde-Langosch and Volkmar M{\"u}ller and Udo Schumacher and Burkhard Brandt and Klaus Pantel and Manfred J{\"u}cker",

note = "Copyright {\textcopyright} 2014. Published by Elsevier Inc.",

year = "2014",

month = may,

day = "1",

doi = "10.1016/j.cellsig.2014.01.018",

language = "English",

volume = "26",

pages = "1021--9",

journal = "CELL SIGNAL",

issn = "0898-6568",

publisher = "Elsevier Inc.",

number = "5",

}

RIS

TY - JOUR

T1 - AKT3 regulates ErbB2, ErbB3 and estrogen receptor α expression and contributes to endocrine therapy resistance of ErbB2(+) breast tumor cells from Balb-neuT mice

AU - Grabinski, Nicole

AU - Möllmann, Katharina

AU - Milde-Langosch, Karin

AU - Müller, Volkmar

AU - Schumacher, Udo

AU - Brandt, Burkhard

AU - Pantel, Klaus

AU - Jücker, Manfred

PY - 2014/5/1

Y1 - 2014/5/1

N2 - ErbB2(+) breast cancer is an aggressive breast cancer subtype generally associated with lower estrogen receptor alpha (ERα) expression and more aggressive tumor behavior compared to ERα(+)/ErbB2(-) breast cancer. The ErbB2(+) phenotype is associated with resistance to endocrine therapy, e.g. the selective estrogen receptor modulator Tamoxifen. However, the mechanisms underlying endocrine resistance are not fully understood. Here, we investigated the impact of AKT signaling and distinct functional roles of AKT isoforms in ErbB2(+) breast cancer from Balb-neuT mice. AKT isoform specific in vitro kinase assays revealed that AKT3 is activated in Balb-neuT breast tumors in comparison to normal murine breast tissue. Knock-down of AKT3, but not of AKT1 or AKT2, led to reduced expression and tyrosine-phosphorylation of ErbB2 and ErbB3 in Balb-neuT-derived mammary tumor cells. In contrast, expression of ERα was strongly up-regulated and phosphorylation of the AKT substrate Foxo3a which regulates ERα transcription was decreased in AKT3 knockdown cells. These data suggest that ERα expression is down regulated via AKT3/Foxo3a signaling in ErbB2(+) breast cancer cells. Furthermore, up-regulation of ERα after depletion of AKT3 resulted in a significant increase in Tamoxifen responsiveness of Balb-neuT-derived mammary tumor cells. In addition, Tamoxifen resistant human breast cancer cell lines showed increased AKT3 expression and activity in comparison to Tamoxifen responsive MCF-7 cells. Finally, by AKT isoform specific in vitro kinase assays of human breast cancer samples, AKT3 activity was detected in ErbB2(+) and triple negative tumors but not in ERα(+) breast cancer. Our data indicate that AKT3 regulates the expression of ErbB2, ErbB3 and ERα and demonstrate that down-regulation of activated AKT3 can sensitize ErbB2(+) breast cancer cells for treatment with Tamoxifen. Therefore, AKT3 targeting might be a new promising strategy for therapy of ErbB2(+)/ERα(-) breast cancer and might further increase the responsiveness to an endocrine therapy approach.

AB - ErbB2(+) breast cancer is an aggressive breast cancer subtype generally associated with lower estrogen receptor alpha (ERα) expression and more aggressive tumor behavior compared to ERα(+)/ErbB2(-) breast cancer. The ErbB2(+) phenotype is associated with resistance to endocrine therapy, e.g. the selective estrogen receptor modulator Tamoxifen. However, the mechanisms underlying endocrine resistance are not fully understood. Here, we investigated the impact of AKT signaling and distinct functional roles of AKT isoforms in ErbB2(+) breast cancer from Balb-neuT mice. AKT isoform specific in vitro kinase assays revealed that AKT3 is activated in Balb-neuT breast tumors in comparison to normal murine breast tissue. Knock-down of AKT3, but not of AKT1 or AKT2, led to reduced expression and tyrosine-phosphorylation of ErbB2 and ErbB3 in Balb-neuT-derived mammary tumor cells. In contrast, expression of ERα was strongly up-regulated and phosphorylation of the AKT substrate Foxo3a which regulates ERα transcription was decreased in AKT3 knockdown cells. These data suggest that ERα expression is down regulated via AKT3/Foxo3a signaling in ErbB2(+) breast cancer cells. Furthermore, up-regulation of ERα after depletion of AKT3 resulted in a significant increase in Tamoxifen responsiveness of Balb-neuT-derived mammary tumor cells. In addition, Tamoxifen resistant human breast cancer cell lines showed increased AKT3 expression and activity in comparison to Tamoxifen responsive MCF-7 cells. Finally, by AKT isoform specific in vitro kinase assays of human breast cancer samples, AKT3 activity was detected in ErbB2(+) and triple negative tumors but not in ERα(+) breast cancer. Our data indicate that AKT3 regulates the expression of ErbB2, ErbB3 and ERα and demonstrate that down-regulation of activated AKT3 can sensitize ErbB2(+) breast cancer cells for treatment with Tamoxifen. Therefore, AKT3 targeting might be a new promising strategy for therapy of ErbB2(+)/ERα(-) breast cancer and might further increase the responsiveness to an endocrine therapy approach.

U2 - 10.1016/j.cellsig.2014.01.018

DO - 10.1016/j.cellsig.2014.01.018

M3 - SCORING: Journal article

C2 - 24463007

VL - 26

SP - 1021

EP - 1029

JO - CELL SIGNAL

JF - CELL SIGNAL

SN - 0898-6568

IS - 5

ER -