Re: Breast Cancer Increases: ...(response to Phillip Bigelow)
Todd A. Farmerie (taf2@po.cwru.edu)
Sun, 24 Nov 1996 22:17:51 -0500
James Howard wrote:
>
> Breast Cancer Increases: ...(response to Phillip Bigelow)
[many snips]
> "I sent my hypothesis of high testosterone and low DHEA in breast cancer to
> the Journal of the American Medical Association, Feb 4, '94. It was rejected.
> This is Mr. Bigelow's reason for responding to me. Mr. Bigelow says:
>
> "A sincere suggestion:
> Post a copy of your submitted AMA research draft on a website
> I guess I will respond to his interest in the letter I sent to the
> "Journal of the American Medical Association."
[end snips]
> "Re: Breast Cancer Increases in the U.S.
>
> Dear Editor:
>
> (Please consider the following as a "Letter to the Editor." It contains 379
> words and two references.)
>
> I suggest the rise in breast cancer results from the same mechanism that
> produces the 'secular trend.'
I am new to this discussion. Is this your term?
> The increases in breast cancer directly parallel
> the secular trend. I think the secular trend is produced by increases in
> testosterone. Testosterone increases size, sexuality, aggression, and, I
> suggest, hastens puberty in both males and females (hallmarks of the trend).
You suggest that it hastens puberty? There is published work on
hyper-androgenemia playing a role in precocious puberty in females, and
I suspect in males. You shouldn't suggest when it is documented.
> In a well-fed society, these individuals will increase in percentage
> exponentially.
What is your evidence for an abundant diet causing an exponential
increase in the percentage of individuals with elevated androgen
levels? (A percent can't increase exponentially very long.)
> I suggest it is this increased testosterone in these women that
> increases breast cancer.
>
> My work suggests transcription and replication of DNA require the hormone,
> dehydroepiandrosterone (DHEA).
I would love to see evidence for this statement. How was this
determined (How did you do the experiments)? Replication and
transcription use (mostly) different collections of enzymatic
reactions. Which of them does DHEA affect (does it regulate something
conserved, such as helicases, or does it have independant effects on the
two processes? Did you expect JAMA to accept this statement without
citation?
> That is, all gene activity competes for
> DHEA. Testosterone causes use of DHEA for testosterone-target tissues. I
> suggest aging results when DHEA naturally begins to decline around 28
> years (aging is loss of support of transcription of DNA). Therefore,
> increased use of DHEA by testosterone tissues advances the decline of
> available DHEA, i.e., testosterone advances aging and the following
> mechanism explains why aging causes cancer.
I suspect that there are those who would argue with your definition of
aging. Do you have any reference for "the loss of support of
transcription of DNA" being used to define aging, or is this yours?
> I suggest activation of genes of cell division require larger amounts of DHEA
> than genes of differentiation.
You suggest? In other words, you have no evidence for this important
step in your logic? What would be the mechanism for this differential
effect? This implies an action through the proteins regulating
transcription. Which ones? (I do see now that your claimed effect on
replication is secondary to a differential effect on transcription.)
> Therefore, as growth occurs, DHEA decreases
> in availability, genes of differentiation then begin to use DHEA, and cell
> division declines.
Genes cannot "use" DHEA. If you want to publish work in a medical
journal, precise language is a must. Why would differentiation NOT be
able to "use" DHEA at the earlier higher concentrations? Competition?
> This is how differentiation competes with, and inhibits,
> cell division.
But by this model, it cannot be inhibiting cell division. If cell
division occurs at higher concentrations of DHEA than the concentration
allowing differentiation, it must be that the more active division at
the higher concentration is inhibiting differentiation (which otherwise
would be going for broke with such high DHEA concentrations). Once the
DHEA levels drop below the threshhold concentration for division, the
differentiation would become dominant. (This is a standard kinetic
model of competition between high affinity-low capacity/low
affinity-high capacity enzymes or receptors, and unless you want to
reinvent kinetics, you had best take such things as Kd and the number of
binding sites into account when working out your model.)
How is it then that differentiation occurs at different times in
different tissues during development and growth? Do each of these
differentiation processes (or more appropriately for your model, the
elimination of transcription of genes for cell division) have a
different DHEA cutoff for activity in each of these different tissues?
> As aging begins, I suggest loss of DHEA begins the opposite
> process. That is, genes of advanced differentiation are closed down in
> reverse order.
You have now shut down all but "housekeeping genes." You are here
suggesting a process whereby differentiation is not terminal, but
requires the continual presence of "differentiation" proteins. Again,
this is a statement that needs referenced.
> For oncogenes to become activated, I suggest transcription
> reversal must include loss of transcription of genes controlling cell adhesion.
Ah, no. There is no requirement for loss of cell adhesion in activation
of oncogenes. All it requires is a point mutation.
> Loss of cell adhesion is characteristic of oncogene function.
You are here reversing cause and effect. Activation of oncogenes causes
dedifferentiation and the reinitiation of cell division, which in turn
results in (and not from) the loss of cell adhesion (this happens during
most cell division, and is used to syncronize cells populations).
> I suggest loss
> of cell adhesion triggers oncogene activity, because it increase the surface
> area of the cell for DHEA absorption. "This" increased DHEA would then be
> able to activate oncogenes.
>
Ah, no. DHEA levels would not change with enough rapidity for surface
area to play any function. The system would be at a relative
equilibrium. No matter what the surface area, you are not going to
change the concentration. (In addition, an increase in DHEA would turn
the "differentiation" genes back on, and return things to the
differentiated state, reactivate the transcription of cell adhesion
proteins, and reverse the increase in surface area - Catch 22.)
> It is known that breast tumors, but not normal breast tissue, concentrate
> DHEA (J. Steroid Biochem. 26: 151, 1987). Measurable levels of DHEA are
> reduced in women with breast cancer, and this reduction in DHEA occurs as
> early as nine years prior to diagnosis (Geriatrics 37: 157, 1982).
I will have to take your word for this, but diagnosis and onset are
different things, so this could be another cause/effect reversal.
> While there
> isn't space here to explain the connection of this mechanism with known
> breast cancer risk factors, one is very clear. Early menstruation, or rather
> early puberty, could be explained by rapid maturation produced by
> testosterone's effect in the midbrain."
By midbrain, I suspect you mean the hypothalamic-pituitary-(gonadal)
axis? If so, you might again be reversing cause and effect. Elevated
gonadotropins can cause increased androgens, which in turn leads to
precocious puberty and ovarian tumors in mice.
I am not surprised that JAMA wanted nothing to do with your letter.
Based on two references (which might confuse cause/effect and do not
address the central premise of your theory), one unreferenced
observation (DHEA affecting transcription of ALL genes), and a whole lot
of speculation, you cure cancer. Perhaps if you first published your
studies of DHEA regulating transcription of all genes, you would find
more buyers. Still you need to show the variable effects of DHEA on the
genes for the cell division vs. those for differentiation (which are
largely different and uncharacterized in various tissues), and also work
out a sensible kinetic scheme if you really want anyone to take your
hypothesis seriously.
Todd
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