Abstract
BACKGROUND: Most breast cancers depend on estrogenic growth stimulation. Functional genetic screenings in in vitro cell models have identified genes, which override growth suppression induced by anti-estrogenic drugs like tamoxifen. Using that approach, we have previously identified Breast Cancer Anti-Estrogen Resistance 4 (BCAR4) as a mediator of cell proliferation and tamoxifen-resistance. Here, we show high level of expression and function of BCAR4 in human breast cancer.
METHODS: BCAR4 mRNA expression was evaluated by (q)RT-PCR in a panel of human normal tissues, primary breast cancers and cell lines. A new antibody raised against C78-I97 of the putative BCAR4 protein and used for western blot and immunoprecipitation assays. Furthermore, siRNA-mediated gene silencing was implemented to study the function of BCAR4 and its downstream targets ERBB2/3.
RESULTS: Except for placenta, all human normal tissues tested were BCAR4-negative. In primary breast cancers, BCAR4 expression was comparatively rare (10%), but associated with enhanced proliferation. Relative high BCAR4 mRNA expression was identified in IPH-926, a cell line derived from an endocrine-resistant lobular breast cancer. Moderate BCAR4 expression was evident in MDA-MB-134 and MDA-MB-453 breast cancer cells. BCAR4 protein was detected in breast cancer cells with ectopic (ZR-75-1-BCAR4) and endogenous (IPH-926, MDA-MB-453) BCAR4 mRNA expression. Knockdown of BCAR4 inhibited cell proliferation. A similar effect was observed upon knockdown of ERBB2/3 and exposure to lapatinib, implying that BCAR4 acts in an ERBB2/3-dependent manner.
CONCLUSION: BCAR4 encodes a functional protein, which drives proliferation of endocrine-resistant breast cancer cells. Lapatinib, a clinically approved EGFR/ERBB2 inhibitor, counteracts BCAR4-driven tumor cell growth, a clinical relevant observation.
Original language | English |
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Article number | e0136845 |
Pages (from-to) | e0136845 |
Journal | PloS one |
Volume | 10 |
Issue number | 8 |
DOIs | |
Publication status | Published - 2015 |
Externally published | Yes |
Keywords
- Adult
- Aged
- Breast Neoplasms/genetics
- Carcinoma, Lobular/genetics
- Cell Line, Tumor
- Cell Proliferation/drug effects
- Female
- Humans
- Lapatinib
- Middle Aged
- Protein Kinase Inhibitors/pharmacology
- Quinazolines/pharmacology
- RNA, Long Noncoding/genetics
- Receptor, ErbB-2/genetics
- Receptor, ErbB-3/genetics