Type

Journal Article

Authors

Leonie S Young
Marie McIlroy
Arnold D K Hill
Peadar O'Gaora
Yuan Hao
Ronan M Conroy
Christopher Byrne
Paul Tibbitts
Fiona Bane
Jean McBryan
and 2 others

Subjects

Biochemistry

Topics
therapeutic use proto oncogene proteins c jun triazoles disease free survival tff1 protein human humans metabolism neoplasm recurrence local tumor suppressor proteins proto oncogene proteins c myc female drug therapy cell line tumor nitriles aromatase inhibitors genetics transcription genetic up regulation biosynthesis estrogen receptor alpha proto oncogene proteins c fos ncoa3 protein human letrozole gene expression regulation neoplastic drug resistance neoplasm pharmacology breast neoplasms jnk mitogen activated protein kinases map kinase signaling system cyclin d1 cell proliferation promoter regions genetic androstenedione nuclear receptor coactivator 3

AIB1:ERα transcriptional activity is selectively enhanced in aromatase inhibitor-resistant breast cancer cells. (2012)

Abstract The use of aromatase inhibitors (AI) in the treatment of estrogen receptor (ER)-positive, postmenopausal breast cancer has proven efficacy. However, inappropriate activation of ER target genes has been implicated in the development of resistant tumors. The ER coactivator protein AIB1 has previously been associated with initiation of breast cancer and resistance to endocrine therapy. Here, we investigated the role of AIB1 in the deregulation of ER target genes occurring as a consequence of AI resistance using tissue microarrays of patients with breast cancer and cell line models of resistance to the AI letrozole. Expression of AIB1 associated with disease recurrence (P = 0.025) and reduced disease-free survival time (P = 0.0471) in patients treated with an AI as first-line therapy. In a cell line model of resistance to letrozole (LetR), we found ERα/AIB1 promoter recruitment and subsequent expression of the classic ER target genes pS2 and Myc to be constitutively upregulated in the presence of both androstenedione and letrozole. In contrast, the recruitment of the ERα/AIB1 transcriptional complex to the nonclassic ER target cyclin D1 and its subsequent expression remained sensitive to steroid treatment and could be inhibited by treatment with letrozole. Molecular studies revealed that this may be due in part to direct steroid regulation of c-jun-NH(2)-kinase (JNK), signaling to Jun and Fos at the cyclin D1 promoter. This study establishes a role for AIB1 in AI-resistant breast cancer and describes a new mechanism of ERα/AIB1 gene regulation which could contribute to the development of an aggressive tumor phenotype.
Collections Ireland -> Royal College of Surgeons in Ireland -> PubMed

Full list of authors on original publication

Leonie S Young, Marie McIlroy, Arnold D K Hill, Peadar O'Gaora, Yuan Hao, Ronan M Conroy, Christopher Byrne, Paul Tibbitts, Fiona Bane, Jean McBryan and 2 others

Experts in our system

1
Leonie S Young
Royal College of Surgeons in Ireland
Total Publications: 42
 
2
Marie McIlroy
Royal College of Surgeons in Ireland
 
3
Arnold D K Hill
Royal College of Surgeons in Ireland
Total Publications: 110
 
4
Peadar O'Gaora
University College Dublin
Total Publications: 11
 
5
Yuan Hao
Royal College of Surgeons in Ireland
Total Publications: 5
 
6
Ronán Conroy
Royal College of Surgeons in Ireland
Total Publications: 150
 
7
Christopher Byrne
Royal College of Surgeons in Ireland
Total Publications: 13
 
8
Paul Tibbitts
Royal College of Surgeons in Ireland
Total Publications: 11
 
9
Fiona T Bane
Royal College of Surgeons in Ireland
Total Publications: 9
 
10
Jean McBryan
Royal College of Surgeons in Ireland
Total Publications: 10