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Perturbation of epithelial apicobasal polarity by rhomboid family‐1 gene overexpression
Author(s) -
Peng XueMei,
Gao Shan,
Deng HuiTing,
Cai HongXing,
Zhou Zhuan,
Xiang Rong,
Zhang QiangZhe,
Li LuYuan
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201800016r
Subject(s) - cell polarity , gene silencing , biology , microbiology and biotechnology , chemistry , gene , cell , cancer research , genetics
The human rhomboid family (RHBDF)1 gene is highly expressed in breast cancer under clinical conditions but not in normal mammary gland tissues. Silencing the RHBDF1 gene in breast cancer xenograft tumors leads to inhibition of tumor growth. We show in this study that artificially raising RHBDF1 protein levels in the mammary epithelial cells MCF‐10A results in severe perturbations of the ability of the cells to form lumencontaining acini, either in 3‐dimensional cell cultures or implanted in mouse mammary fat pads. Knocking down RHBDF1 with short hairpin (sh)RNA leads to restoration of acinus formation. Consistently, RHBDF1 overexpression gives rise to disordered distribution of polarity markers GM130 and laminin‐5, which otherwise are located in apical and basal positions, respectively, in the acini. Further investigations reveal that RHBDF1 directly binds to Par6a, a component of a protein complex consisting of partitioning‐defective scaffold protein (Par)6, Par3, renin‐angiotensin system‐related C3 botulinum toxin substrate (Rac)1, and cell‐ division cycle (Cdc)42, which is structurally critical to the formation of apicobasal polarity. RHBDF1 binding to Par6a results in collapse of the protein complex and thus disruption of polarity formation. Since early stages of breast cancer are characterized by the loss of mammary gland epithelial cell polarity, our findings indicate that perturbations of apicobasal polarity by high levels of RHBDF1 is a significant attribute in the development of breast neoplasia.—Peng, X.‐M., Gao, S., Deng, H.‐T., Cai, H.‐X., Zhou, Z., Xiang, R., Zhang, Q.‐Z., Li, L.‐Y. Perturbation of epithelial apicobasal polarity by rhomboid family‐1 gene overexpression. FASEB J. 32, 5577–5586 (2018). www.fasebj.org