The impact of Ras/MAPK/S6K signaling pathway on prediction ofclinical outcome in metastatic Her-2 positive breast cancerpatients treated with trastuzumab
2014
Background: The overexpression of Her-2 (c-erbB2/Neu) in breast
cancer is associated with poor prognosis, tumor recurrence and
shortened survival. The administration of the trastuzumab
significantly improves patients prognosis. However, in spite of
these successful results, trastuzumab is effective only in
30-50% of cases. PI3K/Akt and Ras/MAPK signaling pathways are
activated through Her-2 receptor and other growth factors’
receptors and both play important role in tumor behavior.
Methods: The study included 76 women with verified Her-2+
metastatic breast cancer (MBC) who were treated with
trastuzumab based palliative chemotherapy. Immunohistochemistry
was performed on formalin fixed, paraffin embedded tissue
sections with antibodies against S6K, p-S6K-Ser235/236, MAPK,
p-MAPK-Thr202/Tyr204, GSK3β, p-GSK3β-Ser9, mTOR,
p-mTOR-Ser2448. The cytoplasmatic and nuclear fractions of the
staining were assessed separately. Results: Patients whose
tumors showed cytoplasmic (c) and nuclear (n) expression of p-
GSK3β-Ser9 exhibited worse PFS compared to tumors with negative
p-GSK3β-Ser9 (PFS 5,1 vs 9,1 months; P=0,006). Similar results
were also found in p-S6K kinase activity, with the difference
that it was possible to observe the dependence on the p-S6K
kinase compartmentalization. Patients whose tumors showed
p-S6K-Ser235/236 expression accompanied with only cytoplasmatic
(c) or nuclear and cytoplasmatic (n+c) staining exhibited worse
PFS compared to tumors with negative p-S6K-Ser235/236
expression (negat) (c vs negat: 6,3 vs 16,1 months, P=0,006;
n+c vs negat: 7,8 vs 16,1 months, P=0,025). Of the remaining
kinases, we showed no effect of their expression on treatment
outcome. Conclusions: This study confirms that prediction of
the response or resistance to trastuzumab treatment depends on
the S6K and GSK3β kinase activity. Patients, whose tumors had
high level of p-S6K or p-GSK3β, had poorer benefit from
trastuzumab based therapy. These patients are candidates for
targeted blockade of PI3K/Akt and/or RAS/MAPK signaling
pathways.
Keywords:
- Correction
- Source
- Cite
- Save
- Machine Reading By IdeaReader
0
References
0
Citations
NaN
KQI