PAX2 & AIB-1 in Taxmoxifen Resistance

[1rarebird]

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]

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 (http://her2support.org/vbulletin/showthread.php?t=43403) link which used TAM+Exemestane+Herceptin. I think green tea (http://her2support.org/vbulletin/showthread.php?t=44079) as well as chromium picolonate may inhibit aromatase. Here (http://her2support.org/vbulletin/showthread.php?t=42381&highlight=issues)'s a portal to endocrine issues.



Nature. (http://javascript%3Cb%3E%3C/b%3E:AL_get%28this,%20%27jour%27,%20%27Nature.%27% 29;) 2008 Dec 4;456(7222):663-6. Epub 2008 Nov 12.
Regulation of ERBB2 by oestrogen receptor-PAX2 determines response to tamoxifen.

Hurtado A (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Hurtado%20A%22%5BAuthor%5D), Holmes KA (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Holmes%20KA%22%5BAuthor%5D), Geistlinger TR (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Geistlinger%20TR%22%5BAuthor%5D), Hutcheson IR (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Hutcheson%20IR%22%5BAuthor%5D), Nicholson RI (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Nicholson%20RI%22%5BAuthor%5D), Brown M (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Brown%20M%22%5BAuthor%5D), Jiang J (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Jiang%20J%22%5BAuthor%5D), Howat WJ (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Howat%20WJ%22%5BAuthor%5D), Ali S (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Ali%20S%22%5BAuthor%5D), Carroll JS (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Carroll%20JS%22%5BAuthor%5D).
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]