Abstract
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.
Highlights
The response rarely sustains long among the responders for Herceptin monotherapy treatment
We have provided a novel mechanism of acquired resistance to Herceptin in human epidermal growth factor receptor 2 (HER2)-positive breast cancer and have resolved the inconsistencies in the literature regarding the effect of Herceptin on HER2 phosphorylation
Using a range of biochemical and cell-biology techniques, we have shown that BRCA1 is modified by SUMO in response to genotoxic stress, and co-localises at sites of DNA damage with SUMO1, SUMO2/3 and the SUMO conjugating enzyme Ubc9
Summary
The response rarely sustains long among the responders for Herceptin (trastuzumab) monotherapy treatment. BRCA1 is strongly implicated in the maintenance of genomic stability by its involvement in multiple cellular pathways including DNA damage signalling, DNA repair, cell cycle regulation, protein ubiquitination, chromatin remodelling, transcriptional regulation and apoptosis Both pathological and gene expression profiling studies provide evidence that breast cancers with germline mutations in BRCA1 are different from non-BRCA1-related breast cancers. The vitreous humour is one of the few tissues in the body that is avascular and virtually acellular, and previous studies have indicated that opticin contributes to the maintenance of this state by inhibition of angiogenesis The aim of this present study is to investigate the effect and mode of action of opticin in suppressing tumour cell proliferation and migration in vitro in a panel of breast cancer cell lines and to establish its therapeutic efficacy in human breast tumour xenografts in vivo. Using receptorselective ligands (patent filed by MRC Technology) specific for the TRAIL death receptors, TRAIL-R1/TRAIL-R2, we have previously shown that primary leukaemic cells isolated from patients with chronic lymphocytic leukaemia can be selectively sensitized to apoptosis by combining an a histone deacetylase inhibitor (HDACi) with a TRAIL-R1-specific form of TRAIL/TRAIL-R1 mAb
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