BACKGROUND: Overexpression and amplification of the human epidermal growth 
factor receptor 2 (HER2) occur in 20% of total breast carcinomas. 
HER2-overexpression is implicated in disease initiation and progression and 
associated with poor prognosis. Trastuzumab, a humanized monoclonal antibody, is 
the standard HER2-targeted therapy for early and metastatic HER2-amplified 
breast cancer patients. Trastuzumab has significantly increased clinical benefit 
in HER2+ metastatic and adjuvant settings; however, it is not effective for many 
patients due to primary or acquired resistance to the drug. During the last 
decade, many studies have revealed a number of novel molecular traits of HER2+ 
breast cancer, allowing us to uncover the molecular mechanisms involved in 
trastuzumab resistance and develop strategies to overcome resistance to therapy.
OBJECTIVE: In this review, we comprehensively addressed the current achievements 
in preclinical studies; we discussed molecular mechanisms of acquired 
trastuzumab resistance in HER2+ breast cancer models and potential therapeutic 
approaches based on the molecular features for HER2+ breast cancer.
CONCLUSION: Enhanced understanding of the molecular profiles in HER2+ breast 
cancer may lead to the identification of novel biomarkers for the development of 
diagnostic approaches and improvement of therapeutic targets for the prevention 
and treatment of trastuzumab resistant HER2+ breast cancer.