A Basis of Breast Cancer Based on Dehydroepiandrosterone (DHEA) and Testosterone; Expanded

Two recent citations regarding connections of "urban," "rural,"neighborhood," and "racial" with breast cancer may support my explanation of female breast cancer. "Neighborhood and racial influences on triple negative breast cancer: evidence from Northeast Ohio," (Breast Cancer Res Treat (2023). https://doi.org/10.1007/s10549-023-06883-6) and "Urban–Rural Disparity in Birth Cohort Effects on Breast Cancer Incidence," (J Urban Health (2023). https://doi.org/10.1007/s11524-023-00718-x)

These 2023 reports regarding breast cancer both consider urban / rural / socioeconomic connections, and race with breast cancer. I suggest these may be explained by the ratio of the androgens dehydroepiandrosterone (DHEA) and testosterone, as I suggested in 1994. Rural / urban areas are characterized by testosterone levels: higher in urban areas.

It is my hypothesis of 1994 that increased testosterone increases breast cancer, as well as other cancers, (International Journal of Cancer 2005; 115: 497). This also explains why breast cancer is increasing; it is my hypothesis that women of higher testosterone are increasing in percentage within populations with time. I also suggest the biological "secular trend," the increase in birth weight and earlier puberty in children is caused by increases in women of higher testosterone. The secular trend is occurring in many places in the world.

The causal mechanism involves testosterone's effects on levels of dehydroepiandrosterone (DHEA). That is, high and low testosterone affect availability of DHEA. I think reductions in DHEA result when increased testosterone occurs early in puberty and and this may occur in the lower socioeconomic levels. Increased testosterone has been connected with reduced learning ability, reduced impulse control, sexuality, and increased negative medical outcomes. All of these reduce the ability to obtain gainful employment and participation in societies increasingly dependent upon advanced educational achievement and personal control. This would concentrate this type of individual within these levels. The concentration mechanism is a higher percentage of females of higher testosterone within these populations.

A report comparing rural areas and a large city found that testosterone is higher in the large city (Folia Histochem Cytobiol. 2001;39 Suppl 2:38-9). This is further supported in American Journal of Human Biology. 2006;18(1):123132: "Men in the most urban group had higher testosterone levels than among groups of farmers and men in informal housing rural areas."

“Black mothers had higher androstenedione and testosterone
concentrations than white mothers.” (Cancer Causes Control 2003; 14: 347-
55) "Serum testosterone was modestly, but significantly, greater in the
black than in the white women." (J Clin Endocrinol Metab 1996; 81: 1023-6.

I suggest increased testosterone may be higher in the lower socioeconomic levels. Again: Increased testosterone has been connected with reduced learning ability, reduced impulse control, sexuality, and increased negative medical outcomes. All of these reduce the ability to obtain gainful employment and participation in a society increasingly dependent upon advanced educational achievement and personal control. This would concentrate this type of individual within these levels. The concentration mechanism is a higher percentage of females of higher testosterone within these populations.

I think testosterone can adversely affect available DHEA in two ways. High testosterone can reduce sulfatase activity. This would reduce conversion of the background source of DHEA, DHEA sulfate, to the active form, DHEA. I think testosterone increases intracellular DHEA by increasing androgen receptors, primarily in the brain. Low testosterone would reduce androgen receptors and reduce intracellular DHEA.

At puberty, testosterone increases which increases growth and development of brain and body in preparation for reproduction. Excess high testosterone at puberty can reduce DHEA and increase the initiation of breast cancer. This could cause earlier breast cancer in black women than white. "Among younger women, Black and non-Hispanic Black women have higher rates of breast cancer compared to white and non-Hispanic white women. Among older women, white and non-Hispanic white women have higher rates of breast cancer compared to Black and non-Hispanic Black women." (https://www.komen.org/breast-cancer/risk-factor/race-ethnicity/ ).

Since testosterone increases intracellular DHEA, the higher testosterone of black women may extend this mechanism into older ages, whereas, in older white women, this would result in reduced intracellular DHEA.

Testosterone levels affect DHEA availability.

The mechanism I produced in 1994, is based on exposure of oncogenes. I suggest DHEA levels positively affect cell adhesion. Reduced DHEA would reduce cell adhesion. Reduced cell adhesion would expose cells of tissues to increased individual cellular surface area. This would expose some tissue cells to increased nutrient availability as well as to increased DHEA. In a reduced DHEA situation within the body, I think this exposure of increased cell surface would significantly increase relative levels of DHEA, compared to their normal tissue state. I suggest this would expose cells containing oncogenes to increased viability. Oncogenes could become active.

High testosterone of an earlier age could reduce DHEA which would reduce cell adhesion which would increase possible oncogene activity. High testosterone would be selected by evolution because it would increase the onset of puberty and sexual activity.

Early, high testosterone would result in earlier puberty and result in an earlier, larger subsequent decline of testosterone. It is known that both DHEA and testosterone are reduced by pregnancy. Since testosterone is involved in increasing intracellular DHEA, an earlier, deeper decline in testosterone would also reduce available DHEA and the exposure of oncogenes. In men "A dose-dependent maintenance of mRNA concentration for E-Cad was observed throughout the epididymis of orchidectomized rats after replacement with testosterone." ( Endocrinology, Volume 130, Issue 1, 1 January 1992, Pages 353–363, https://doi.org/10.1210/en.130.1.353 ) DHEA was not mentioned in this report.

DHEA naturally declines with age, reaching very low levels in old age. "Age is the highest risk factor for developing a majority of cancers, with a few exceptions." (https://www.roswellpark.org/cancertalk/202006/does-cancer-risk-increase-age ).

James Michael Howard, Fayetteville, Arkansas, USA

The importance of DHEA and Testosterone to Human evolution. I think mammalian evolution occurred because of selection for DHEA and human evolution because of selection for testosterone because testosterone increases intracellular DHEA primarily in the brain. This caused "gracilization," the increase in brain size at the expense of the body, a hallmark of human evolution. This is seen in the fossil record in Homo erectus in which sexual dimorphism is reduced by increased female size without a decreased male size. The increase in female size is the key evolutionary change. Increased female testosterone directly affected fetal brain growth and development.

("Hormones in Mammalian Evolution," Rivista di Biologia / Biology Forum 2001; 94: 177-184. If your library does not subscribe to "Rivista ... ," you may find this at: http://anthropogeny.com/Hormones%20in%20Mammalian%20Evolution.htm .)

(Androgens in Human Evolution, Rivista di Biologia / Biology Forum 2001; 94: 345-362. If your library does not subscribe to Rivista , you may find this at: http://anthropogeny.com/Androgens%20in%20Human%20Evolution.htm where you may also see a chart of testosterone in humans and great apes which directly supports my hypothesis and was reported in the literature 2 years later.)