Estrogen and prostate cancer: An eclipsed truth in an androgen‐dominated scenario

Abstract

Prostate cancer is the commonest non-skin cancer in men. Incidence and mortality rates of this tumor vary strikingly throughout the world. Although several factors have been implicated to explain this remarkable variation, lifestyle and dietary factors may play a dominant role, with sex hormones behaving as intermediaries between exogenous factors and molecular targets in development and progression of prostate cancer. Human prostate cancer is generally considered a paradigm of androgen-dependent tumor; however, estrogen role in both normal and malignant prostate appears to be equally important. The association between plasma androgens and prostate cancer remains contradictory and mostly not compatible with the androgen hypothesis. Similar evidence apply to estrogens, although the ratio of androgen to estrogen in plasma declines with age. Apart from methodological problems, a major issue is to what extent circulating hormones can be considered representative of their intraprostatic levels. Both nontumoral and malignant human prostate tissues and cells are endowed with key enzymes of steroid metabolism, including 17betahydroxysteroid dehydrogenase (17betaHSD), 5beta-reductase, 3alpha/3betaHSD, and aromatase. A divergent expression and/or activity of these enzymes may eventually lead to a differential prostate accumulation of steroid derivatives having distinct biological activities, as it occurs for hydroxylated estrogens in the human breast. Locally produced or metabolically transformed estrogens may differently affect proliferative activity of prostate cancer cells. Aberrant aromatase expression and activity has been reported in prostate tumor tissues and cells, implying that androgen aromatization to estrogens may play a role in prostate carcinogenesis or tumor progression. Interestingly, many genes encoding for steroid enzymes are polymorphic, although only a few studies have supported their relation with risk of prostate cancer. In animal model systems estrogens, combined with androgens, appear to be required for the malignant transformation of prostate epithelial cells. Although the mechanisms underlying the hormonal induction of prostate cancer in experimental animals remain uncertain, there is however evidence to support the assumption that long term administration of androgens and estrogens results in an estrogenic milieu in rat prostates and in the ensuing development of dysplasia and cancer. Both androgen and estrogen have been reported to stimulate proliferation of cultured prostate cancer cells, primarily through receptor-mediated effects. As for estrogens, the two major receptor types, ERalpha and ERbeta, are expressed in both normal and diseased human prostate, though with a different cellular localization. Since these two receptors are different in terms of ligand binding, heterodimerization, transactivation, and estrogen response element activity, it is likely that an imbalance of their expression may be critical to determine the ultimate estrogen effects on prostate cancer cells. In prostate canc...

Alcohol and smoking and subsequent risk of prostate cancer in Japanese men: The Japan Public Health Center‐based prospective study

“…25,26 Furthermore, accumulating evidence suggests that prostate carcinogenesis by alcohol is mediated through increased estrogens and decreased androgens and sex hormone-biding globulin. [27][28][29][30][31][32] Results regarding the effect of smoking on prostate cancer have been inconsistent. Our present results showed that smoking decreased the risk of prostate cancer in total subjects, but that this negative association might have been impaired in subjects whose cancer was detected by subjective symptoms.…”

Prevention of Prostate Cancer with Vitamins - Current Perspectives

“…Additionally, presence of estrogens and insulin like growth factor (IGF-I) in milk has been hypothesized to be associated with risk of prostate cancer (Carruba, 2007;Weaver, 2009). But even five cups of milk/day would supply about only 1.3 mg calcium/day, which is too low to produce any significant impact on plasma estrogen concentration (Weaver, 2009).…”

Análise da expressão de receptores hormonais (androgênio, estrogênio alfa e beta) e da aromatase em carcinomas epidermóides de boca (CE)

“…Além disso, tem se associado a expressão local da aromatase e síntese de estrogênio ao crescimento de neoplasias benignas, como o leiomioma uterino e de neoplasias malignas como: câncer de endométrio, útero, próstata (Cunat et al, 2004;Cheng et al, 2006;Ishida et al, 2007;Czajica-Oraniec;Simpson, 2010) e da cavidade bucal (Cheng et al, 2006;Ishida et al, 2007) O estrogênio possui dois tipos de receptores, α e β (REα e REβ), codificados respectivamente por genes diferentes: ESR1 e ESR2, encontrados em locais cromossômicos diferentes (Bord et al, 2001;Carruba, 2007). Ambos apresentam alto grau de homologia no domínio de ligação de DNA, porém diferem consideravelmente no domínio N terminal e no domínio E. Essas diferenças sugerem que esses dois receptores apresentem funções distintas para as respostas biológicas e na regulação da transcrição gênica sob o comando do estradiol (Bardin et al, 2004).…”

“…Ambos apresentam alto grau de homologia no domínio de ligação de DNA, porém diferem consideravelmente no domínio N terminal e no domínio E. Essas diferenças sugerem que esses dois receptores apresentem funções distintas para as respostas biológicas e na regulação da transcrição gênica sob o comando do estradiol (Bardin et al, 2004). O modo de ação de cada receptor depende da quantidade e do nível da expressão encontrada de cada um dele nos tecidos (Bord et al, 2001;Carruba, 2007).…”

“…Acredita-se que o desequilíbrio entre a quantidade de receptores alfa e beta nos órgãos reprodutivos possa estar relacionada ao surgimento de neoplasias (Fixemer et al, 2003, Bardini et al, 2004, Carruba, 2007.…”