Regulation of ERBB2 by oestrogen receptor-PAX2 determines response to tamoxifen.
Crosstalk between the oestrogen receptor (ER) and ERBB2/HER-2 pathways has long been implicated in breast cancer aetiology and drug response, yet no direct connection at a transcriptional level has been shown. Here we show that oestrogen-ER and tamoxifen-ER complexes directly repress ERBB2 transcription by means of a cis-regulatory element within the ERBB2 gene in human cell lines. We implicate the paired box 2 gene product (PAX2), in a previously unrecognized role, as a crucial mediator of ER repression of ERBB2 by the anti-cancer drug tamoxifen. We show that PAX2 and the ER co-activator 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 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.
Hurtado
Antoni
A
Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.
Holmes
Kelly A
KA
Geistlinger
Timothy R
TR
Hutcheson
Iain R
IR
Nicholson
Robert I
RI
Brown
Myles
M
Jiang
Jie
J
Howat
William J
WJ
Ali
Simak
S
Carroll
Jason S
JS
D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004967:Estrogens / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020868:Gene Silencing; D018734:Genes, erbB-2 / Q000235:genetics*; D051548:Histone Acetyltransferases; D006801:Humans; D056921:Nuclear Receptor Coactivator 3; D051762:PAX2 Transcription Factor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D011960:Receptors, Estrogen / Q000378:metabolism*; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics; D012097:Repressor Proteins / Q000378:metabolism; D013629:Tamoxifen / Q000378:metabolism / Q000494:pharmacology*; D015534:Trans-Activators
D004967:Estrogens; D051548:Histone Acetyltransferases; D056921:Nuclear Receptor Coactivator 3; D051762:PAX2 Transcription Factor; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D012097:Repressor Proteins; D013629:Tamoxifen; D015534:Trans-Activators; C538866:NCOA3 protein, human