Cross talk between the Estrogen Receptor (ER) and ErbB2/HER-2 pathways have long been implicated in breast cancer aetiology and drug response 1 , yet no direct connection at a transcriptional level has been shown. We now show that estrogen-ER and tamoxifen-ER complexes directly repress ErbB2 transcription via a cis-regulatory element within the ERBB2 gene. We implicate the Paired Box 2 gene product (Pax2), in a novel role, as a crucial mediator of ER repression of ErbB2 by the anti-cancer drug tamoxifen. We show that Pax2 and the ER coactivator AIB-1/SRC-3 compete for binding and regulation of ErbB2 transcription, the outcome of which determines tamoxifen response in breast cancer cells. The repression of ErbB2 by ER-Pax2 links these two important breast cancer subtypes and suggests that aggressive ErbB2 positive tumours can originate from ER positive luminal tumours by circumventing this repressive mechanism. These data provide mechanistic insight into the molecular basis of endocrine resistance in breast cancer.The genomic mapping of Estrogen Receptor binding sites has revealed insight into how ER functions in breast cancer cells, including the finding that ER rarely binds to promoter regions and that ER loading on the chromatin requires the presence of pioneer factors, such as FoxA1 2-4 . We have replicated genome-wide ER Chromatin Immunoprecipitation (ChIP)-on-chip analyses in ER positive MCF-7 cells. Identification of the ER binding sites using a false discovery rate of 5% revealed 8,525 ER sites, with excellent representation (86%) of the published ER binding profile 2 (Supplementary data 2). Included within the new, more extensive list, was an ER binding site within the intron of the ERBB2/HER-2 genomic region ( Figure 1a). Sequence analysis of all 8,525 ER binding sites revealed a statistical enrichment (p-value < 0.0001) for the Paired Box (Pax) transcription factor motif (GTCANGN(A/G)T) ( Figure 1b). Little is known about the role that Pax proteins play in hormone signalling, however, Pax2 was shown to be expressed in a subset of breast cancers and was recently identified as a tamoxifen-regulated effector in endometrial cancer cells 5,6 .5 To whom correspondence should be addressed (jason.carroll@cancer.org.uk). NIH Public Access Author ManuscriptNature. Author manuscript; available in PMC 2010 August 11. Tamoxifen is one of the most successful and effective therapies in the treatment of breast cancer, but tamoxifen resistance is inevitable 7 . Tamoxifen resistant breast tumours are characterised by elevated ErbB2 levels 8 and ER positive cell line models over expressing ErbB2 acquire resistance to tamoxifen 9 . We assessed Pax2 binding to a select number of ER binding sites adjacent to important estrogen regulated genes, including the newly identified binding site within the ERBB2 gene. Pax2 was generally recruited only after tamoxifen treatment, with the exception of the ER binding site within ERBB2 (Figure 1c), where Pax2 was recruited to the ER binding site after both estrogen and tamoxifen...

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Ion channels are involved in normal physiologic processes and in the pathology of various diseases. In this study, we investigated the presence and potential function of transient receptor potential melastatin 7 (TRPM7) channels in the growth and proliferation of FaDu and SCC25 cells, two common human head and neck squamous carcinoma cell lines, using a combination of patch-