complicated new article on the origins/pathways gone awry in Inflammatory BC

[Lani]

ABSTRACT: NF-?B activation in inflammatory breast cancer is associated with oestrogen receptor downregulation, secondary to EGFR and/or ErbB2 overexpression and MAPK hyperactivation [British Journal of Cancer]
Activation of NF-?B in inflammatory breast cancer (IBC) is associated with loss of estrogen receptor (ER) expression, indicating a potential crosstalk between NF-?B and ER. In this study, we examined the activation of NF-?B in IBC and non-IBC with respect to ER and EGFR and/or ErbB2 expression and MAPK hyperactivation. A qRT-PCR based ER signature was evaluated in tumours with and without transcriptionally active NF-?B, as well as correlated with the expression of eight NF-?B target genes. Using a combined ER/NF-?B signature, hierarchical clustering was executed. Hyperactivation of MAPK was investigated using a recently described MAPK signature (Creighton et al, 2006), and was linked to tumour phenotype, ER and EGFR and/or ErbB2 overexpression. The expression of most ER-modulated genes was significantly elevated in breast tumours without transcriptionally active NF-?B. In addition, the expression of most ER-modulated genes was significantly anticorrelated with the expression of most NF-?B target genes, indicating an inverse correlation between ER and NF-?B activation. Clustering using the combined ER and NF-?B signature revealed one cluster mainly characterised by low NF-?B target gene expression and a second one with elevated NF-?B target gene expression. The first cluster was mainly characterised by non-IBC specimens and IHC ER+ breast tumours (13 out of 18 and 15 out of 18 respectively), whereas the second cluster was mainly characterised by IBC specimens and IHC ER- breast tumours (12 out of 19 and 15 out of 19 respectively) (Pearson ?2, P<0.0001 and P<0.0001 respectively). Hyperactivation of MAPK was associated with both ER status and tumour phenotype by unsupervised hierarchical clustering using the MAPK signature and was significantly reflected by overexpression of EGFR and/or ErbB2. NF-?B activation is linked to loss of ER expression and activation in IBC and in breast cancer in general. The inverse correlation between NF-?B activation and ER activation is due to EGFR and/or ErbB2 overexpression, resulting in NF-?B activation and ER downregulation.

[Lani]

hope this helps

[Roz]

I found this quite hard to follow Lani, but thank you for posting it. I am ER+ and IBC. I was 56 when diagnosed, 5 years past menopause. I am wondering whether or not I should have my ER tested again, as I have a sneaking suspicion that I might have only a little bit of +. If I read this article correctly, ER downregulation should mean ER-??

[Lani]

(although it can be)

In general according to Dr.Mark Pegram, one of the authors of the original article, all her2+ breast cancers have less ER than their measured ER
% would seem to indicate. This seems to be either because the way we measure ER is not the most accurate (I have posted on this before) or because ER percentage is correct but the hormonal sensitivity (the reason ER is tested) of those tumors that are her2 positive is decreased. A recent article I read said this may be because of AKT activation because of her2 or other downstream signalling systems, and in fact this seems to be a major way that other ER+ tumors escape the effects not only of tamoxifen , but even faslodex.

Here there seems to be a similar effect involving EGFR, her2, MAPK, NFKbeta and ER expression (inverse relationship) but the question seems to be what is the chicken and what is the egg and is there a feedback loop?