PAX2 & AIB-1 in Taxmoxifen Resistance

1rarebird · 03-15-2010, 11:22 AM

I've read that for Her2+/ER+ patients, Tamoxifen hormonal therapy doesn't work very well if the patients also have low levels of the PAX2 protein and/or high levels of the protein AIB-1. I believe the AIB-1 somehow interferes with proper functioning of the PAX2-Her2 receptor pathway. That raises questions for me:

1.) Are some doctors testing Her2+/ER+ patients for their levels of PAX2 and AIB-1 proteins, when deciding which hormonal therapy to use (AIs or SERMs)?

2.) Are there ways (drugs or CAMs) that can help raise the PAX2 or knock down the AIB-1 levels?

bird

Rich66 · 03-15-2010, 11:46 AM

Haven't heard much about this. Seems like clinically available testing is pretty limited to what's done in research. If I understand the below, simultaneously inhibiting aromatase may reduce TAM resistance. I know I just posted a bit on this in the endocrine+endocrine link which used TAM+Exemestane+Herceptin. I think green tea as well as chromium picolonate may inhibit aromatase. Here's a portal to endocrine issues.

Nature. 2008 Dec 4;456(7222):663-6. Epub 2008 Nov 12.
Regulation of ERBB2 by oestrogen receptor-PAX2 determines response to tamoxifen.

Hurtado A, Holmes KA, Geistlinger TR, Hutcheson IR, Nicholson RI, Brown M, Jiang J, Howat WJ, Ali S, Carroll JS.
Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.
Erratum in:

Nature. 2009 Feb 26;457(7233):1168.

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.

PMID: 19005469 [PubMed - indexed for MEDLINE]