S6 kinase signaling and tamoxifen response in breast cancer cells and in two randomized breast cancer cohorts

• Detecting signals in the mammalian target of rapamycin (mTOR), and the estrogen receptor (ER) pathways for prediction of treatment response may be a future clinical tool in primary breast cancer. Here, we investigated the validity and value of the mTOR targets p70-S6 kinase (S6K) 1 and 2 as biomarkers for tamoxifen sensitivity in vitro and in two independent tamoxifen randomized postmenopausal breast cancer cohorts. In addition, the prognostic value of the S6Ks was evaluated. A simultaneous knockdown of the S6Ks in ER-positive breast cancer cells resulted in G1 arrest, and tamoxifen-induced G1 arrest was in part S6K1+S6K2 dependent, suggesting separate roles in proliferation and in tamoxifen response. We found S6K1 to correlate with HER2 and cytoplasmic Akt activity, whereas S6K2 and phosphorylated S6K were closer connected with ER positivity, low proliferation and nucleic p-Akt. Treatment prediction and prognosis were evaluated by immunohistochemical staining. Nuclear accumulation of S6K1 was indicative of a reduced tamoxifen treatment effect, compared with a significant benefit from tamoxifen treatment in patients without tumor S6K1 nuclear accumulation. Patients with a combination of S6K1 nuclear accumulation and S6K2 cytoplasmic accumulation in the tumor cells had no tamoxifen benefit. Also, S6K1 and S6K2 activation, indicated by p-S6K-t389 expression, was associated with low benefit from tamoxifen compared with untreated patients. In addition, high protein expression of S6K1, independent of localization, predicted worse prognosis. This was not evident for variations in S6K2 or p-S6K-t389 expression.In conclusion, the mTOR targeted kinases S6K1 and S6K2 interfere with proliferation and response to tamoxifen. Monitoring their activity andintracellular localization may provide biomarkers for breast cancer treatment, allowing for identification of a group of patients less likely tobenefit from tamoxifen and thus in need of an alternative or additional treatment.

Nyckelord

pS6K

S6K1

S6K2

mTOR

Akt

estrogen receptor

endocrine treatment

MEDICINE

MEDICIN

Publikations- och innehållstyp

vet (ämneskategori)

ovr (ämneskategori)