Common soil of smoking-associated and hormone-related cancers: estrogen deficiency

Abstract

Accumulation of non-smoker, non-drinker elderly postmenopausal female patients among smokingassociated oral cancer cases raised the plausible idea: estrogen deficiency maybe a cancer risk factor. On the other hand, the extremely rare cases of young women with oral cancer regularly exhibited hormonal disorders, such as irregular menstrual cycles and infertility. Furthermore, in the history of middle-aged female, oral cancer cases a primary ovarian failure or complete hysterectomy was a conspicuously frequent finding suggestive of an estrogen deficient milieu. There were many striking contradictions concerning the associations of female sexual steroids and cancer risk as well. Until now, breast and endometrial cancers were regarded as typically estrogen-induced tumors, particularly in postmenopausal cases. However, unexplained beneficial anti-cancer effects of hormonereplacement therapy were reported against cancers at several sites, even tumors of the highly hormone-responsive organs. Re-evaluation of results of the experimental and epidemiological studies, which endeavored to justify the carcinogenic capacity of estrogen, exhibited many shortcomings and controversies. The new findings both on smoking associated and on hormone related cancers added up to the same conversion; not estrogen but rather its deficiency might provoke cancer initiation. Thorough review of the literary data justified that the exquisite regulatory capacity of estrogen and its surveillance on growth, development, differentiation, and metabolism are indispensable, whereas an estrogen-deficient milieu may induce a breakdown in gene-regulation. Recognition of the anticancer capacity of estrogen may provide new insights into the etiology of malignancies and leads to new strategies for cancer prevention and cure.

Circulatory Estrogen Level Protects Against Breast Cancer in Obese Women

“…Equilibrium of sexual hormone production and the development of regular cycles are prerequisites not only for reproduction but also for somatic health in women [19, 20, 136]. Pathological alterations in the critical period of puberty, such as obesity endangering both the fertility and survival of women might not be protective against cancer initiation in either pre- or postmenopausal cases.…”

“…In premenopausal cases, slight or moderate decrease in circulating female sexual steroid levels may be enough to block the delicate mechanism of ovulation. At the same time, a slightly estrogen deficient milieu confers preferential cancer risk for the female organ triad having high estrogen demand [19, 136]. …”

Triple-negative breast cancer risk in women is defined by the defect of estrogen signaling: preventive and therapeutic implications

“…The breast cancer risk of women after hysterectomy may be high, attributed to the abrupt, shocking estrogen deprivation 43. A follow-up study on hysterectomized cases and controls justified the significantly lower risk of breast cancer in the estrogen-treated group of women 55…”

“…Even this slightly estrogen-deficient milieu may confer preferential risk for breast cancer as well as for endometrial and ovarian malignancies in anovulatory women. These female organs have the highest estrogen demand so as to preserve their structural and functional integrity 33,43…”

Diverse pathomechanisms leading to the breakdown of cellular estrogen surveillance and breast cancer development: new therapeutic strategies

“…Difficulties in either the synthesis of estrogens or ER signal transduction mechanisms may increase the risk of clinically diagnosable diseases 31,32…”