PLU-1/Jarid1B contributes to estrogen-induced cell proliferation in the normal mammary gland and in breast cancer, and is required for embryonic survival

PLU-1/Jarid1B is a nuclear protein that is widely expressed in breast cancer, with higher levels being seen in ER⁺ cancers. Expression in normal adult issues is largely restricted to testis and the differentiating mammary gland. Through the JmjC domain the protein can demethylate H3K4me3, which correlates with its function as a transcriptional repressor. PLU-1/Jarid1B contains a DNA binding domain, and can be recruited to DNA through binding to transcription factors. We now find that the protein interacts with the ERα receptor and contributes to estrogen-induced survival of MCF-7 cells in in vitro culture and when grown as tumours in nude mice.

To investigate the function of Plu-1/Jarid1B in vivo, transgenic mice expressing defective Plu-1/Jarid1B have been developed. The systemic KO is an embryonic lethal with no homozygote embryos being detected at day 7.5. Another strain expressing the protein missing the ARID AT-rich DNA binding domain (which is also required for demethylase function) shows a mammary phenotype. In these ΔARID mice, the development of the mammary tree at puberty and early pregnancy is delayed, but the gland recovers by late pregnancy. The inhibition of development of terminal end buds at puberty, which is crucially dependent on ERα signalling, suggests an involvement of Plu-1/Jarid1B in this signalling that is impaired in the ΔARID mouse. Confirming this, levels of expression of downstream targets of ERα (progesterone receptor and Wnt4) are reduced in the ΔARID mouse. The development of spontaneous mammary tumours in the ΔARID mouse is delayed compared with wild-type mice, suggesting that Plu-1/Jarid1B contributes to tumour growth, and that this action is impaired when the ARID domain is deleted.

The data suggest that PLU-1/JARID1B is involved in estrogen-induced growth of normal and malignant mammary epithelial cells.