Growth factor receptor/steroid receptor cross talk in trastuzumab-treated breast cancer.
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.
Endocrine Oncology Research, Department of Surgery, Royal College of Surgeons in Ireland, Dublin, Ireland.
D C
DC
Collins
Endocrine Oncology Research, Department of Surgery, Royal College of Surgeons in Ireland, Dublin, Ireland.
S
S
Cocchiglia
Endocrine Oncology Research, Department of Surgery, Royal College of Surgeons in Ireland, Dublin, Ireland.
P
P
Tibbitts
Endocrine Oncology Research, Department of Surgery, Royal College of Surgeons in Ireland, Dublin, Ireland.
G
G
Solon
Endocrine Oncology Research, Department of Surgery, Royal College of Surgeons in Ireland, Dublin, Ireland.
F T
FT
Bane
Endocrine Oncology Research, Department of Surgery, Royal College of Surgeons in Ireland, Dublin, Ireland.
J
J
McBryan
Department of Mass Spectrometry Unit, Royal College of Surgeons in Ireland, Dublin, Ireland.
A
A
Treumann
Department of Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland.
A
A
Eustace
Department of Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland.
B
B
Hennessy
Endocrine Oncology Research, Department of Surgery, Royal College of Surgeons in Ireland, Dublin, Ireland.
A D
AD
Hill
Endocrine Oncology Research, Department of Surgery, Royal College of Surgeons in Ireland, Dublin, Ireland.
L S
LS
Young
D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000737:chemistry / Q000188:drug therapy*; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D056985:Nuclear Receptor Co-Repressor 2 / Q000502:physiology; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology; D020239:Receptor Cross-Talk / Q000502:physiology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis / Q000502:physiology*; D011960:Receptors, Estrogen / Q000032:analysis / Q000502:physiology*; D000068878:Trastuzumab; D000071163:Trefoil Factor-1; D025521:Tumor Suppressor Proteins / Q000032:analysis
D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D056985:Nuclear Receptor Co-Repressor 2; D047428:Protein Kinase Inhibitors; D016271:Proto-Oncogene Proteins c-myc; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D000068878:Trastuzumab; D000071163:Trefoil Factor-1; D025521:Tumor Suppressor Proteins; C489427:MYC protein, human; C539130:NCOR2 protein, human; C051838:TFF1 protein, human; C508053:ERBB2 protein, human