Trastuzumab is regarded as the primary
therapy for patients with HER2-enriched
breast cancer, but the pathological complete response for advanced cases is less than 30%. The underlying mechanism of
trastuzumab resistance remains unclear and there are currently no conclusive
biomarkers for patient response to
trastuzumab. Identifying predictive
biomarkers for
trastuzumab response may allow treatments to be individually tailored and optimized multi-target
therapies may be developed.
CTMP activates AKT signaling in
breast cancer and over-activation of AKT has been reported to contribute to
trastuzumab resistance. In this study, we examined samples from 369 patients to investigate the correlation between
CTMP expression level and patient outcome. Elevated
CTMP expression was correlated with adverse outcomes in HER2-enriched patients including overall and disease-free survival as well as
trastuzumab resistance. Ectopic expression of varying levels of
CTMP in SkBR3 cells dose-dependently attenuated
trastuzumab-mediated growth inhibition through AKT activation. In addition, inhibition of AKT signaling by
AKT inhibitor IV and
Rapamycin reversed
CTMP-mediated
trastuzumab resistance. In clinical samples, the high expression of
CTMP was showed in
trastuzumab non-responders and positively correlated with AKT activity. Taken together, we demonstrated that
CTMP promotes AKT activation resulting in
trastuzumab resistance in patients with HER2-enriched
breast cancer. High
CTMP expression not only predicted poor prognosis, but may also predict resistance to
trastuzumab in HER2-enriched patients. Therefore,
CTMP expression may be considered as a prognostic
biomarker in HER2-enriched
breast cancer and high expression may indicate a utility for AKT-inhibition in these patients.