ABSTRACT
Treatment with tyrosine kinase inhibitors (TKIs) including trastuzumab has revolutionized the management of HER2-positive breast cancer. Recent evaluation of clinical trial data suggests that a subset of HER2/ER double-positive cancers may not receive significant benefit from the TKI therapy. Here we investigate the cross talk between HER2 and ER in breast cancer and monitor the effect of trastuzumab on the tyrosine kinase effector transcription factor Myc. In HER2-positive breast cancer patients treated with neoadjuvant trastuzumab, steroid receptor-negative status (ER and PR negative) of pre-treatment biopsies predicted pathological complete response (pCR) (n=31 patients, P=0.0486), whereas elevated Myc protein inversely associated with pCR (P=0.0446). Liquid chromatography mass spectrometry identified the corepressor SMRT as a novel Myc-interacting protein. Trastuzumab treatment enhanced Myc-SMRT interactions in HER2-overexpressing breast cancer cells (LCC1) and inhibited expression of the Myc target gene survivin. In HER2-low, ER-positive steroid-dominant cells (MCF7), trastuzumab therapy repressed Myc-SMRT interactions and upregulated survivin expression. Trastuzumab treatment induced ER-CBP interactions, enhanced ER transcriptional activity and upregulated expression of the ER target gene pS2. The absence of pS2 expression in pre-treatment biopsies predicted pCR to neoadjuvant trastuzumab in breast cancer patients (n=25, P=0.0089) and pS2 expression associated with residual cancer burden (P=0.0196). Furthermore, metastatic tissues from patients who had failed trastuzumab therapy were pS2 positive. In HER2-overexpressing cells, trastuzumab treatment can repress Myc transcriptional activity and clinical response is favorable. However, with co-expression of the steroid pathway, this inhibition is lost and response to treatment is often poor.
Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Agents/therapeutic use , Breast Neoplasms/drug therapy , Protein Kinase Inhibitors/therapeutic use , Receptor Cross-Talk/physiology , Receptor, ErbB-2/physiology , Receptors, Estrogen/physiology , Breast Neoplasms/chemistry , Female , Humans , MCF-7 Cells , Nuclear Receptor Co-Repressor 2/physiology , Proto-Oncogene Proteins c-myc/physiology , Receptor, ErbB-2/analysis , Receptors, Estrogen/analysis , Trastuzumab , Trefoil Factor-1 , Tumor Suppressor Proteins/analysisABSTRACT
PURPOSE: The purpose of this study was to report a case of vitreoretinal traction masqueraded as retinal vasculitis. METHODS: An 81-year-old woman with exudative age-related macular degeneration was treated with intravitreal injections of ranibizumab. During routine follow-up, angiographic evidence of focal, segmental, retinal vasculitis, involving both arteries and veins, was noticed in the fellow eye. Clinical examination revealed no sign of ocular inflammation in either eye. RESULTS: Spectralis optical coherence tomography revealed partial posterior vitreous detachment with multiple areas of persisting vitreoretinal adhesion. Focal vasculitis on fluorescein angiography showed absolute correspondence with sites of vitreoretinal traction on optical coherence tomography. Patient was managed by observation and 6 months later, despite persisting fluorescein leak, she was still asymptomatic with no evidence of anterior chamber or vitreous activity. CONCLUSION: This is an exceptional case of pseudovasculitis associated with mechanical traction, representing a variant of vitreomacular traction syndrome. Clinicians should be aware of this unusual manifestation, which may mimic true vasculitis associated with uveitis.
