Can Diabetes Change the Intrinsic Subtype Specificity of Breast Cancer?
Abstract
Luminal type A and type B breast cancers represent estrogen receptor alpha (ER )-positive breast cancers with luminal type A associated with better prognosis. A transcription factor network comprising GATA-3, FOXA1 and ER dictates estrogen (E2) dependence of luminal type A breast cancer. Signaling molecules that disrupt this network may play a role in E2- independence. T-bet is a major negative regulator of GATA-3. As the expression of some of the above factors are controlled by insulin, the objective of this study was to investigate the ability of insulin, as in type II diabetes, to disrupt GATA- 3:FOXA1:ER network. Insulin induced the expression of T-bet in MCF-7 breast cancer cells and MCF-7 cells engineered to overexpress T-bet (MCF-7-T-bet) were anti-estrogen resistant in the presence of insulin. E2-inducible expression of XBP-1, an ER :FOXA1:GATA3 downstream target, was attenuated in MCF-7-T-bet cells compared to parental cells suggesting disruption of this hormonal network by T-bet. MCF-7 cells that have acquired resistance to anti-estrogens overexpressed T-bet and expressed lower levels of FOXA1 compared to parental cells. Importantly, Oncomine database search revealed T-bet overexpression in a subgroup of ER -positive breast cancers, suggesting a role for T-bet in modulating ER activity in a subset of ER -positive breast cancers. MCF-7 -xenograft studies with or without experimentally induced diabetes are currently underway to recapitulate in vitro observations in an in vivo setting.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2008
- Accession Number
- ADA492747
Entities
People
- Harikrishna Nakshatri
- Kasi R. Mccune
Organizations
- Indiana University