Estrogen Effect on Initiation Growth and Progression of Prostate Cancer

While androgens play essential roles in the development and growth of prostate and pathogenesis of prostate cancer, extensive in vivo and in vitro studies suggested that estrogens are required for carcinogenesis of prostate cancer. It was demonstrated that treatment with both estrogen and testosterone will induce 100% dorsolaterol prostate carcinoma in rats.77 In human, direct estrogen effects and the balance of androgens and estrogens may contribute to these estrogen activities. Men synthesize both estrogens and androgens and as men age, the plasma levels of androgen decreases while estrogen remains constant. However, the expression pattern and activity of aromatase, the enzyme that turns testosterone into estrogen, suggests that local synthesized estrogen may have significant consequences in tumorigenesis of prostate.78'79 Here we will focus on estrogens effects on prostate cancer cells from in vitro and in vivo approaches. While this approach provides some insights to explain the in vivo observation from clinical and mouse study, many unclear and controversial data remain.

In prostate, estrogen induced cancerous transformation may be partially due to their genotoxic metabolites, including 2-hydroxy-estrogens, 4-hydroxy-estrogens, quinone, and semiquinone intermediates. These metabolites may directly induce genomic damage or function via formation of reactive oxygen species (ROS).80'81 In addition, the enzymes responsible for the formation or inactivation of these estrogen metabolites may also play critical roles in the estrogen mediated transformation in prostate. These enzymes include (1) cytochrome p4501A1, which can convert estrogen into 2-hydroxy-estrogens, (2) cytochrome p4501B1, which can concert estrogens to 4-hydroxy-estrogens, (3) cathecol-O-methyl-transferase, which can inactivate 2- and 4-hydroxy-estrogens, and (4) glutathione-S-transferases that detoxify ROS.81-83 Although these may be important factors for estrogen mediated effects in prostate, few of them have been investigated for their contribution in prostate cancer.

As the aromatase can convert androgens into estrogens, thus it could be one of the risk factor of prostate cancer.84,85 However, the aromatase transgenic mice and knockout mice have numerous endocrine defects,34,86 thus these mice cannot be used as good models to study the relationship between estrogen formation and prostate cancer risk. The studies will be advanced by producing mice with prostate specific expression or knockout of aromatase in the future.

In adult WT mice, administration of high-dose DES, a potent synthetic estrogen, causes regression of the prostate and induces SQM in the epithelium. The reduced organ size is associated with declining androgen levels, whereas SQM is considered to be a direct, ERa mediated response to estrogen.44 Prostatic SQM is characterized by proliferation of basal cells, leading to formation of stratified squamous epithelium and altered CK10 synthesis. In mouse prostate, DES treatment induces PR synthesis in secretory epithelial cells, which is usually low in the untreated prostate.

Although studies suggested that estrogens are required for carcinogen-esis of prostate cancer, yet extensive evidences also suggest that estrogens can suppress prostate cancer growth. It has been found that estrogen inhibits the cell growth of PC-3, an androgen independent prostate cancer cell line,9 while it can stimulate the growth of LNCaP, an androgen responsive prostate cancer cell line.10 This difference may be due to different ER forms and ER levels in these two cell lines85'86 and other mechanisms. Although estrogen stimulates both ERa and ERp, it is generally believed that ERa stimulates cell proliferation whereas ERp counteracts ERa activity. In the prostate, ERa is exclusively expressed in stroma, while ERp is largely expressed in epithelial cells. In tumors, ERa is expressed in both stroma and epithelial. Many studies support the expression pattern of ERa and ERp, and the interaction between stroma and epithelial of prostate largely contributes to the different estrogen effects on the prostate cancer cells growth in vivo and in vitro.11,87-89 However, the expression pattern of ERa and ERp in normal and tumor prostate tissue, and prostate cancer cell lines are different. More studies need to be elucidated.

The effect of estrogen regulation of prostate cancer cell growth was also tested with the estrogen metabolite, 2-methoxyestradiol (2-ME), which can arrest the cell cycle and induce apoptosis.90,91 However, the 10 (xM dose of 2-ME used in the study is much higher than physiological concentration. Cellular component concentrations are another important factor for the cellular growth or signal. Homeostatic changes might also contribute to malignant growth. Estrogen can increase intracellular Ca (2+) in PC-3 cells.92 Estrogen also reduces the uptake of rubidium chloride, suggesting an estrogen effect on ion transport and change of cellular membrane permeability.93

Although estrogen effects on prostate cancer cell growth are somewhat controversial, the fact that estrogen is required for prostate carcinogenesis is consistent. It was reported that a low ratio of androgen to estrogen results in a higher risk for the prostate cancer. In vivo animal studies also supported that estrogen, in a milieu of decreasing androgen, contributes significantly to the prostate hyperplasia, prostate dysplasia, and prostate cancer. (3ERKO mice cannot be induced by estrogen treatment to grow prostate cancer.76,94 Therefore, estrogens and ERs, together with androgen, are required for the pathogenesis of prostate cancer. Recently, telomerase, whose activity increased during tumorigenesis, has been shown to be stimulated by estrogen in primary cultured cells from BPH and normal prostate tissue. Telomerase contains ERE in its promoter, thus could be a target gene of ER.27 This may be one of the mechanisms by which estrogens stimulate carcinogenesis. Antiestrogen treatment therefore may prevent prostate cancer.

It is very significant that in the transgenic adenocarcinoma mouse prostate (TRAMP) mouse model of adenocarcinoma of the ventral prostate,95 the selective estrogen receptor modulator (SERM), toremifene,96 and the phytoestrogen genistein,97 prevent the development of cancer. Although it has been suggested that this protection results from inhibition of ERa in the prostate stroma, an equally acceptable explanation is that these agents, acting as ERp agonists, prevent proliferation of the prostate epithelium. Such a mechanism is likely in view of the role of ERp in preventing proliferation of the ventral prostate epithelium in the mouse and strongly suggests a role for ERp agonists in the treatment and/or prevention of prostate cancer.

Implantation of prostate cancer xenografts (LuCaP 35, LuCaP 49, LuCaP 58, LuCaP 73, PC-3, and LNCaP) into intact and ovariectomized female mice was done by Corey et al. to characterize growth and uptake rates in the absence of androgens.98 Significant inhibition of prostate cancer growth in intact vs. ovariectomized female animals was observed in five of six prostate cancer xenograft lines (except for PC-3). E2 supplements given to ovariectomized female mice led to inhibition of tumor establishment and diminished growth of LuCaP 35, similar to that observed in intact female mice. RT-PCR showed that these xenografts express the ERp message. Two hypothetical mechanisms may be suggested to explain how E2 can affect prostate cancer tumor growth in female mice in the absence of androgens: (1) E2 exerts direct inhibitory effects via ER expressed on prostate cancer cells or via other, as yet unidentified, mechanisms; and (2) E2 exerts effects on other cells, which then secrete signaling molecules that inhibit prostate cancer growth.

Together, these in vivo and in vitro studies suggested that estrogens may have dual roles: (1) estrogens are required for tumorigenecity of prostate cancer; and (2) Estrogens may suppress growth of prostate cancer.

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