BCAR4 induces antioestrogen resistance but sensitises breast cancer to lapatinib

• Published in: British journal of cancer Vol. 107; no. 6; pp. 947 - 955
• Main Authors: Godinho, M F E, Wulfkuhle, J D, Look, M P, Sieuwerts, A M, Sleijfer, S, Foekens, J A, Petricoin, E F, Dorssers, L C J, van Agthoven, T
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 04.09.2012; Nature Publishing Group
• Subjects: 631/67/1059/2326; 692/53/2423; 692/699/67/1347; 692/700/565/1436/1437; Adult; Aged; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Antineoplastic Agents, Hormonal - therapeutic use; Biological and medical sciences; Biomarkers, Tumor - analysis; Biomedical and Life Sciences; Biomedicine; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Breast Neoplasms - mortality; Cancer Research; Cell Proliferation; Clinical Study; Disease-Free Survival; Drug Resistance; Drug Resistance, Neoplasm; Epidemiology; Estrogen Receptor Modulators - therapeutic use; Female; Gene Expression Regulation, Neoplastic - drug effects; Gynecology. Andrology. Obstetrics; Humans; Mammary gland diseases; Medical sciences; Middle Aged; Molecular Medicine; Molecular Targeted Therapy - methods; Oncology; Phosphorylation - drug effects; Protein Kinase Inhibitors - therapeutic use; Quinazolines - pharmacology; Quinazolines - therapeutic use; Receptor, ErbB-2 - drug effects; Receptor, ErbB-2 - genetics; Receptor, ErbB-2 - metabolism; Receptors, Estrogen - analysis; Reverse Transcriptase Polymerase Chain Reaction; RNA, Long Noncoding; RNA, Messenger - metabolism; RNA, Untranslated - drug effects; RNA, Untranslated - genetics; RNA, Untranslated - metabolism; Signal Transduction - drug effects; Tamoxifen - therapeutic use; Tumors; targeted therapy; breast cancer; BCAR4; tamoxifen resistance; ERBB2; Antineoplastic agent; Breast disease; Targeted therapy; Antiestrogen; erbB2 Gene; Antihormone; Selective estrogen receptor modulator; Cancerology; Lapatinib; Non steroid compound; Protein-tyrosine kinase; Protooncogene; Enzyme; Tyrosine kinase inhibitor; Transferases; Enzyme inhibitor; Breast cancer; Malignant tumor; Tamoxifene; Human Epidermal growth factor Receptor 2; Resistance; Mammary gland diseases; Treatment; C-Onc gene; Cancer
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/bjc.2012.351

Background: High BCAR4 and ERBB2 mRNA levels in primary breast cancer associate with tamoxifen resistance and poor patient outcome. We determined whether BCAR4 expression sensitises breast cancer cells to lapatinib, and identifies a subgroup of patients who possibly may benefit from ERBB2-targeted therapies despite having tumours with low ERBB2 expression. Methods: Proliferation assays were applied to determine the effect of BCAR4 expression on lapatinib treatment. Changes in cell signalling were quantified with reverse-phase protein microarrays. Quantitative reverse-transcriptase polymerase chain reaction (RT–PCR) of ERBB2 and BCAR4 was performed in 1418 primary breast cancers. Combined BCAR4 and ERBB2 mRNA levels were evaluated for association with progression-free survival (PFS) in 293 oestrogen receptor- α (ER)-positive patients receiving tamoxifen as first-line monotherapy for recurrent disease. Results: BCAR4 expression strongly sensitised ZR-75-1 and MCF7 breast cancer cells to the combination of lapatinib and antioestrogens. Lapatinib interfered with phosphorylation of ERBB2 and its downstream mediators AKT, FAK, SHC, STAT5, and STAT6. Reverse transcriptase–PCR analysis showed that 27.6% of the breast cancers were positive for BCAR4 and 22% expressed also low levels of ERBB2 . The clinical significance of combining BCAR4 and ERBB2 mRNA status was underscored by the finding that the group of patients having BCAR4 -positive/ ERBB2 -low-expressing cancers had a shorter PFS on tamoxifen treatment than the BCAR4 -negative group. Conclusion: This study shows that BCAR4 expression identifies a subgroup of ER-positive breast cancer patients without overexpression of ERBB2 who have a poor outcome and might benefit from combined ERBB2-targeted and antioestrogen therapy.