Breast Cancer Anti-Estrogen Resistance 4 (BCAR4) Drives Proliferation of IPH-926 lobular Carcinoma Cells.

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.

• Authors: Ton van Agthoven, Lambert C J Dorssers, Ulrich Lehmann, Hans Kreipe, Leendert H J Looijenga, Matthias Christgen
• Journal: PloS one (PLoS One) Vol. 10 Issue 8 Pg. e0136845 ( 2015) ISSN: 1932-6203 [Electronic] United States
• PMID: 26317614 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• BCAR4 non-coding RNA, human
• Protein Kinase Inhibitors
• Quinazolines
• RNA, Long Noncoding
• Lapatinib
• ERBB2 protein, human
• ERBB3 protein, human
• Receptor, ErbB-2
• Receptor, ErbB-3

Topics

• Adult
• Aged
• Breast Neoplasms (genetics, metabolism, pathology)
• Carcinoma, Lobular (genetics, metabolism, pathology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Female
• Humans
• Lapatinib
• Middle Aged
• Protein Kinase Inhibitors (pharmacology)
• Quinazolines (pharmacology)
• RNA, Long Noncoding (genetics, metabolism)
• Receptor, ErbB-2 (genetics, metabolism)
• Receptor, ErbB-3 (genetics, metabolism)