DHEA, Growth and Development, Cancer, and Death
Copyright 2006, James
It is my hypothesis that low dehydroepiandrosterone (DHEA) may trigger breast cancer (1994) (Annals of Internal Medicine 2005; 142: 471-472). My primary hypothesis is that DHEA optimizes replication and transcription of DNA, therefore, all tissues, including cancer, rely on optimum levels of DHEA. When DHEA is plentiful, replication of DNA is favored; as DHEA availability declines, transcription increases. As DHEA availability further decreases, transcription of various genes increases. So, as cells divide, as cells form large clumps, DHEA availability is decreased per cell and simple growth is decreased as differentiation increases. As cells form into tissues, reduction of cell surface area regulates availability of DHEA within cells. I suggest it is this regulation of DHEA levels within cell groups that directs differentiation of tissues. That is, differing levels of DHEA within differing cells results in differential transcription of DNA. Different genes are activated by different levels of DHEA.
A basic control mechanism which must exist to form tissues is expression of genes of cell adhesion. Cell adhesion genes must be activated early when DHEA availability begins to decline in order to keep early cells together. Therefore, on the way to becoming tissues, cell adhesion produces “pro-tissues.” This results in reduced cell surface areas through which nutrients, etc., including DHEA, is controlled. I suggest it is this level of DHEA and the pathway already followed by the cells of pro-tissues which results in a specific type of gene expression (transcription) which produces the final tissue. Again, as DHEA availability is reduced, different genes are activated. Cells in groups will express similar gene expression.
In an adult organism, if DHEA levels decline sufficiently, cellular DHEA absorption is reduced. DHEA naturally declines in old age; most cancer formation is in the elderly. I suggest that, in some cells, reduction in DHEA results in reduced expression of genes controlling cell adhesion. Therefore, low DHEA reduces cell adhesion and the cell surface of these cells increases. This increases absorption of DHEA. As DHEA levels increase, the ratio of DHEA activation of transcription to replication begins to reverse. That is, in these cells, some genes, perhaps “oncogenes,” are activated and begin to use the DHEA at the expense of genes of cell adhesion. The cells begin to replicate. Hence, it is my suggestion that low DHEA may result in activation of cells which contain genes of cell duplication that are activated simultaneously with loss of cell adhesion. This may explain cancer formation. Since cancer also relies on DHEA, this may explain why cancers, though more frequent in old age, grow less rapidly in old age. Cancers that form in young people, grow rapidly because of higher DHEA but they are rare. They are rare, I suggest, because their high DHEA reduces “low DHEA-induced” cancers.
DHEA may reverse the transformation of cancer. Treatment with DHEA reduces growth of malignant cell lines and increases apoptosis (cell death) (J Gastroenterol 2005; 40: 490-7), suppresses mammary carcinogenesis by changing gene expression and inducing cellular senescence (Breast Cancer Res 2005; 7: R1132-40) and reduces tumor growth (J Endocrinol 2006; 188: 321-31). I suggest treatment of these cells with increased DHEA causes competition within the genes and competition between the genes of differentiation and duplication of the cell. That is, treatment with DHEA may cause the cell to “try” to differentiate, again or cause excess expression of genes. This may produce a chaotic situation that may stop simple growth. Cell death, or senescence or apoptosis, may occur because of insufficent DHEA to maintain the cell or too much DHEA. Metastasis may result from total loss of cell adhesion or it may be that low DHEA triggers similar expression of cancer in distant tissues that contain similar oncogenes.
Low DHEA may trigger oncogene activation in different tissues. Hence, low DHEA may activate many kinds of cancer.