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You are here: Home: BCU 6|2002: Supplement
: Daniel F Hayes, MD
DR DANIEL HAYES
DR LOVE: Going back to the overall model of the
estrogen receptor that you were talking about and the model that
you described with SERMs and fulvestrant, a couple of questions.
One is, going back to that model with the corepressors/coactivators,
etcetera, in your mind, what happens to that system when the patient
or the tumor becomes resistant to the SERM?
DR HAYES: Again,
let’s be very careful. Let’s assume that the cancer
is still hormone-dependent, but has now become resistant to the
SERM. So, what’s the mechanism of that resistance? We don’t
know for sure, but this, again, is where people like Craig Jordan,
Kent Osborne and Suzanne Fuqua have been working very hard, also
Rob Nicholson, to try to explain it. One possibility is that they
begin to upregulate things like HER2 and epidermal growth factor
receptor, and they get constitutive phosphorylation of the estrogen
receptor, so that you get constitutive dimerization and then activation
independent of the ligand. So, now you can throw all the ligand
in you want. It doesn’t matter. The ER’s already doing
what it wants to do.
DR LOVE: But it is a genetic, evolutionary change?
DR HAYES: I think
all of these are going to be so-called genetic, evolutionary changes.
The hallmark of cancer, of course, is replication and chromosomal
instability, and genomic instability. These cancers keep changing
on the basis of the fact that they can’t control the stability
of their genome, and you get all kinds of weird mutations. Coldman
and Goldie predicted years ago – what’s it been? Twenty-five
years ago now – that you would get, based on this –
they didn’t know about P-53. They didn’t know about
the keepers of the genome – but they predicted that the hallmark
of a cancer would be genetic instability, because they knew there
were a lot of chromosomal abnormalities, and that you’d get
mutations to and away from sensitivity and resistance. So, it’s
not like the cancer cell is thinking up ways to become resistant.
The cancer cell is just genetically unstable. Every time it divides,
it makes mistakes. Some of those mistakes are prone to sensitivity;
some of those mistakes are prone to resistance. The sensitivity
allows us to treat it, but, of course, the resistance is what gives
us problems.
DR LOVE: So, you’re saying one possible
mechanism for that resistance, would be activation of the HER system?
DR HAYES: So, one
possibility is activation of the HER.
DR LOVE: What’s the relationship between
the HER system and the ER system?
DR HAYES: It looks
like, as far as we can tell, the peptide growth factors, in general
– and the HER system is probably the best example of this
– are responsible for this phosphorylation. They’re
the things that lead to a cascade of phosphorylating events down
through a signal transduction pathway, and ultimately the ER is
one of the targets. So, the ER is sitting around waiting to be activated.
The way it’s activated in the wild type is it has to have
a ligand, estrogen, and when the ligand binds to the ER, it then
seems to be conformationally susceptible to phosphorylation. When
it’s not bound to its ligand, it doesn’t seem to be.
But one way of getting resistance, therefore, is to figure out,
teleologically speaking, how to become phosphorylated in the absence
of ligand. Because then you’re off to the races, if you’re
an estrogen receptor.
DR LOVE: And then once it becomes phosphorylated
it activates the gene?
DR HAYES: It’s
not going to be this easy. It’s like we were 15 years ago.
DR LOVE: You’ve got to make it easy. (Laughter)
DR HAYES: We thought
it was going to be easy 15 years ago, and every time I’m at
a meeting like this, I learn five more things. But it looks like
phosphorylation and dimerization are the keys to binding to the
DNA, to the estrogen response element in the DNA in the promoter
region of the gene of interest. So one way to get there might be
to figure out how to be phosphorylated and dimerized without a ligand.
DR LOVE: But then, if that were the case, you
would think that, then, for example, if you lowered the level of
ligands, say, with an aromatase inhibitor or an LHRH agonist, that
it wouldn’t have any effect if the HER2 system bypassed it.
DR HAYES: So that
may not be an effect.
DR LOVE: So, how would you explain?
DR HAYES: I’m
speculating now.
DR LOVE: Okay.
DR HAYES: So, that’s
one. Another might be mutating your ER so that it now becomes hypersensitive
to individual ligands. If that’s the case, then what you said
would be precisely what you’d expect, which is that ligand-based
therapy, the SERMs, might suddenly start acting like estrogens;
whereas, ligand-annihilating or depleting therapy, like oophorectomy
or LHRH agonist or antagonist and the aromatase inhibitors might
still be affective. Again, you’ve still got a hormone-dependent
cell, and it’s now, if you will, searching even more for its
ligand, than it used to. So smaller doses of the ligand or maybe
even a ligand that used to be anti-estrogenic now are super-estrogenic,
so, depletion would completely remove it.
The other is perhaps that phosphorylation makes the receptor super-responsive
to the ligand. So, again, in that case ligand-depletion might be
just what you want to do. This brings in when do you use fulvestrant?
Because it’s neither A nor B. It’s ligand therapy that
essentially is a suicide ligand, if you will. It binds to the ER
and keeps all the downstream stuff from happening.
DR LOVE: You mentioned suicide because the ER
is lost from the cell?
DR HAYES: Yeah. I
guess suicide is a bad word.
DR LOVE: Well, but the bottom line is, the ER
goes away, so to speak. Why does that happen?
DR HAYES: Well, because
there’s a constant turnover in the estrogen receptor. I guess
it’s not so much that it disappears, per se. That’s
probably part of the natural process of the turnover, but that,
while it’s there, it’s completely inactivated, because
it can’t dimerize.
DR LOVE: But it is kind of weird that you actually
lose it from the cell, at least the way we measure it.
DR HAYES: Yeah, it
looks like it. I think Craig Allred might be able to give you a
better answer than I can on that.
DR LOVE: Speaking of Craig Allred, another question
I had as you were talking about this biology is, what is the current
thinking in terms of to what extent this whole system is altered
in the basic development of breast cancer? I mean, is it an alteration
in the estrogen receptor system and all these coactivators that
really is the essential defect that you see in breast cancer? Craig
has shown that you see, I think, actually more ER in early stages
of carcinogenesis than in the normal development.
DR HAYES: Well, I
think one of the things that’s evolving – I guess a
fundamental question is – are all breast cancers estrogen-receptor-positive
from the get-go, and then estrogen-receptor-negative cancers evolve
out of those? Or, are there fundamentally two kinds of breast cancers
from the get-go, and one is estrogen-dependent and the other one’s
estrogen-independent?
I think it’s sort of a mixture of those, but I believe, from
the get-go, there are fundamentally two cells that become malignant.
Again, this is where some of the work from Craig Allred and others
are beginning to tell us, of course, that not every epithelial cell
in the breast is endocrine-dependent in the wild-type breast. In
the normal breast, some are, some aren't. We really don’t
know what the stem cell is for the development of any epithelial
cancer, let alone breast cancer, but I think another area of really
active research is trying to find the epithelial stem cell. I believe,
in the next five years, you’re going to see that area explode.
There are laboratory studies going on now, some of which are published,
some of which are not, that are going to tell us what actually becomes
cancer, what the cell is that becomes cancer.
I think what we’re going to find is that from long before
we call it cancer, when it’s ADH or even before we call it
ADH, there are cells dedicated to becoming cancer, that are estrogen-independent,
and cells dedicated to becoming cancer that are estrogen-dependent.
And I think that’s where the two flavors of cancer grow out
from, those that are ER-independent and those that are ER-dependent.
Now, I think the ones that are estrogen-dependent, ultimately,
the patients we don’t cure unfortunately, do become estrogen-independent.
But I think that’s probably actually much farther down the
road, as you get more and more genetic instability and finally you
begin to get clones growing out that no longer need hormones to
grow and divide and do all the things they want to do. But I think
that’s actually a pretty late event.
Early on, I think there are two cancers to start with, and this
raises, I think, issues of preventive strategies and treatment strategies.
We focus an awful lot on the hormone-dependent cancers, which we
should. Clearly, breast cancer has something to do with estrogen.
I’m fond of telling my patients that when I was 17, I began
to realize that the female hormone system confused me, as I was
dating, and now that I’m 50, it really confuses me. It’s
very complex. And clearly, breast cancer has something to do with
the estrogen and the female endocrine system, but we don’t
understand it entirely. In fact, we don’t understand a lot
of it. We don’t know does estrogen really cause breast cancer?
We know it’s associated with an increased risk of breast cancer,
but we don’t know that it exogenous estrogen causes breast
cancer.
DR LOVE: Looking at Craig Allred’s work,
sometimes I’ve had the thought that maybe what the problem
is, is the estrogen receptor itself, like more estrogen receptor
or being more sensitive to estrogen.
DR HAYES: Well, people
have tried to call estrogen receptor an oncogene. Are there fundamental
defects in the estrogen receptor that lead to the oncogenic process?
And that’s been hard to do. We’ve not found –
Suzanne Fuqua may be the closest to that now, with these mutations,
and the estrogen receptor becomes hypersensitive to estrogen. But
I think that we need a lot of work on that.
DR LOVE: Well, maybe part of this co-repressor/activator
mix?
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