ER+ breast tumors may involve ER-independent mechanisms of gene activation
 

It keeps getting more complex!

It helps explain why targeted drugs are only likely to be partially successful.

I found this a while ago but did not appreciate its significance.

In terms of seeking solutions it underlines the need for a broad approach including diet.

My admiration and a happy and healthy new year to all


RB




http://www.ncbi.nlm.nih.gov/entrez/q...15&query_hl=10


1: Hum Mol Genet. 2003 Dec 15;12(24):3245-58. Epub 2003 Oct 21. Related Articles, Links


Classifying the estrogen receptor status of breast cancers by expression profiles reveals a poor prognosis subpopulation exhibiting high expression of the ERBB2 receptor.

Kun Y, How LC, Hoon TP, Bajic VB, Lam TS, Aggarwal A, Sze HG, Bok WS, Yin WC, Tan P.

National Cancer Centre, Singapore, Republic of Singapore.

Recent work using expression profiling to computationally predict the estrogen receptor (ER) status of breast tumors has revealed that certain tumors are characterized by a high prediction uncertainty ('low-confidence'). We analyzed these 'low-confidence' tumors and determined that their 'uncertain' prediction status arises as a result of widespread perturbations in multiple genes whose expression is important for ER subtype discrimination. Patients with 'low-confidence' ER+ tumors exhibited a significantly worse overall survival (P=0.03) and shorter time to distant metastasis (P=0.004) compared with their 'high-confidence' ER+ counterparts, indicating that the 'high-' and 'low-confidence' binary distinction is clinically meaningful. We then discovered that elevated expression of the ERBB2 receptor is significantly correlated with a breast tumor exhibiting a 'low-confidence' prediction, and this association was subsequently validated across multiple independently derived breast cancer expression datasets employing a variety of different array technologies and patient populations. Although ERBB2 signaling has been proposed to inhibit the transcriptional activity of ER, a large proportion of the perturbed genes in the 'low-confidence'/ERBB2+ samples are not known to be estrogen responsive, and a recently described bioinformatic algorithm (DEREF) was used to demonstrate the absence of potential estrogen-response elements (EREs) in their promoters. We propose that a significant portion of ERBB2's effects on ER+ breast tumors may involve ER-independent mechanisms of gene activation, which may contribute to the clinically aggressive behavior of the 'low-confidence' breast tumor subtype.

PMID: 14570715 [PubMed - indexed for MEDLINE]

Does this mean if you are highly er+ you have a better prognosis than someone who has lower er+ status?

Greek to me
 

Good question Karenann. What in the world does this mean? Some of these articles, although I am sure very relevant mean nothing to most of us because they are in a language we cannot understand. How much do we really want to add to our confusion? I prefer to add to my understanding and knowledge, so if someone can interpret this, thank you.

Here is the link to the full article which may help. The little box did not copy across.

I too do not understand much of it. The article recognises gaps in knowledge. It does undeline the complexity of it all.

Is it not raising the possibility of a grey area between ER+ and ER-, and even "crosstalk" between the two? Would that not have treatment and diagnostic implications. Might it not go someway to putting some shred of explanation where there are diagnostic difficulties between ER+ and ER-

I take your point about adding to knowledge. It was either post it as it was or not post it as I do not have sufficeint knowledge to "translate" it.

If somebody can translate this into simple terms with certainty please help.

http://hmg.oxfordjournals.org/cgi/co...ull/12/24/3245

My first reaction is HUH??
My second is I'm er- and what I decipher scares me.
And 3rd, I plan to make a copy and let my onc. read it.
Carol

And-- does this mean that you're more likely to be er- if you are her2 positive?
Carol
I'm confused

I'll tell you what...just when I think I am understanding what this report is saying, I get confussed all over again. When they use the term, low confidence and high confidence, are they referring to a person who is, er+ 45% (low confidence) and er+95% (high confidence)?

I think I'll have my husband take a look and see what he has to say.

Karen

Carol,

I am er/pr+ (highly er+ and weakly pr+) and when I found out that I was Her2+++, one of the nurses in my bc support group told me that it was, unusual to be er/pr+ and Her2+++. She said that most Her2+++ bc is er/pr-. However, there are 5 women in my support group who are Her2+++, 3 of whom are er/pr+ as well. I also read a report (wish I could find it now) that said 30% - 40% of all Her2+++ bc is also er/pr+.

Karen

Thanks, Karen.
It's interesting that the support group I went to did not have one other person who was her2 positive and there were probably 12-14 people. I felt like sort of a leper.
I've heard the term triple negative-- does that mean er-,pr-and her2 - ??
I think I should just back off a little from all this info, it's freaking me out, especially since I don't understand all of it. Every time I go for Herceptin ( every 3 weeks) I'm armed with lots of questions and the usual answer I hear is--" but even if blah,blah,blah, the treatment would be the same ".
They really don't like to get into the stats or prognostical stuff.
Probably just as well, I'd sleep less than I'm sleeping now if they did.!!!
Thanks again for your info,
Carol

Carol,

Yes, triple negative means, er/pr- and her2-. You made a comment that in your support group, there were no other women who were Her2+++. We were pretty shocked in our group, when we found out there were 5 of us out of 15 who were Her2+++. I was the one who brought it to our attention, explaining that only 20% to 30% of bc is Her2+++.

Interestingly enough, most doctors in this area were not testing for Her2 in early stage bc. Their theory was, that, Herceptin was not being used for early stage bc, so they didn't need to test. When all of the trial results came out, I insisted that they test me and then, so did several other women in my support group. I probably still wouldn't know if I hadn't pushed! Maybe some of the women in your group have not been tested either.

Karen

Karen,
I'll have to ask my onc. if they test everyone early stage or not. I believe they probably do. I was diagnosed in March of '04 when the trials were incomplete. I was stage 2 with 4/18 ax. nodes positive. I was 9 months out of standard chemo when the trials were over and started herceptin in June of '05. As far as I know will continue for another six months for a full year treatment.
What stage were you and are you on herceptin now??
Carol

I am the only Her 2 + person in my support group (there are at least 25 active women but the older survivors do not know their status as 15-25 years ago they were not tested). Our group leader was not hormone positive and she is a 17 year survivor (7 positive nodes). But she does not know if she was Her 2 either or a triple negative.


A 25 yr survivor was on the tamoxifen trial (where she was on an arm that got one year of tamoxifen vs 2 years vs no tamoxifen). She knows she was at least ER + as that was tested as a criteria of the trial (much like Her 2+ is a criteria for Herceptin or Tykerb). I felt that was very interesting in that there was less (readily available) information when going into a trial than there is today (since we have the internet and each other).

I think the paper that this thread started on discuss low confidence and high confidence not in how many receptors are present on the cell surface (ie: 40% ER positive versus 90% ER +) but rather if those receptors bind estrogen strongly or not and if not, then they may differ to other mechanisms for growth (ie: the Her family signaling or other things that we don't know or fully understand yet). This is how I interpret this particular work.

Best wishes

Becky