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. 2010 Oct 15;127(8):1748-57.
doi: 10.1002/ijc.25207.

Effects of estrogen on breast cancer development: Role of estrogen receptor independent mechanisms

Wei Yue  1 , Ji-Ping Wang, Yuebai Li, Ping Fan, Guijian Liu, Nan Zhang, Mark Conaway, Hongkun Wang, Kenneth S Korach, Wayne Bocchinfuso, Richard Santen
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Effects of estrogen on breast cancer development: Role of estrogen receptor independent mechanisms

Wei Yue et al. Int J Cancer. .
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Abstract

Development of breast cancer involves genetic factors as well as lifetime exposure to estrogen. The precise molecular mechanisms whereby estrogens influence breast tumor formation are poorly understood. While estrogen receptor alpha (ERalpha) is certainly involved, nonreceptor mediated effects of estradiol (E(2)) may also play an important role in facilitating breast tumor development. A "reductionist" strategy allowed us to examine the role of ERalpha independent effects of E(2) on mammary tumor development in ERalpha knockout (ERKO) mice bearing the Wnt-1 oncogene. Exogenous E(2) "clamped" at early follicular and midluteal phase levels (i.e., 80 and 240 pg/ml) accelerated tumor formation in a dose-related fashion in ERKO/Wnt-1 animals (p = 0.0002). Reduction of endogenous E(2) by oophorectomy (p < 0.001) or an aromatase inhibitor (AI) (p = 0.055) in intact ERKO/Wnt-1 animals delayed tumorigenesis as further evidence for an ER-independent effect. The effects of residual ERalpha or beta were not involved since enhancement of tumor formation could not be blocked by the antiestrogen fulvestrant. 17alpha-OH-E(2), a metabolizable but ER-impeded analogue of E(2) stimulated tumor development without measurable uterine stimulatory effects. Taken together, our results suggest that ER-independent actions of E(2) can influence breast tumor development in concert with ER dependent effects. These observations suggest 1 mechanism whereby AIs, which block E(2) synthesis, would be more effective for breast cancer prevention than use of antiestrogens, which only block ER-mediated effects.

Figures

Figure 1
Whole mounts of the mammary gland in ERα knockout (ERKO) animals cotransfected with the Wnt-1 gene (ERKO/Wnt-1, top panels) and in ERα positive wild-type animals bearing the Wnt-1 gene (ER+/+/Wnt-1, bottom panels). The entire mammary fat pad is shown with the central lymph node (dense blue) shown on each whole mount for orientation. Three to six animals from each group were examined and morphology of the mammary gland within each group was highly consistent. The groups include: intact: animals in which the ovaries have not been removed surgically; ovx: animals in which the ovaries have been removed surgically before day 16 of life; ovx + E2: animals whose ovaries have been surgically removed but received E2 with silastic implants designed to produce plasma levels of 240 pg/ml; and ovx + E2 + ICI: animals having undergone surgical removal of the ovaries and receiving E2 implants (240 pg/ml) plus fulvestrant (ICI, 5 mg/mouse/week).
Figure 2
Kaplan–Meier curves comparing the effect of estradiol on tumor formation in oophorectomized, ERKO/Wnt-1 animals treated either with cholesterol (vehicle, n = 20) or with silastic implants producing plasma midluteal phase levels of estradiol (240 pg/ml, n = 20) or early follicular phase levels (80 pg/ml, n = 19). The differences between the vehicle-treated animals and those with plasma E2 levels clamped at 240 pg/ml were statistically significant (p = 0.0002). The animals with levels clamped at 80 pg/ml exhibited tumor development curves intermediate between those in the vehicle treated and those receiving 240 pg/ml.
Figure 3
(a) Kaplan–Meier curves of tumor formation in noncastrate ER+/+/Wnt-1 (n = 79) and ERKO/Wnt-1 animals (n = 120) and the effect of oophorectomy performed before 16 days of age on tumor formation in ERKO/Wnt-1 animals (n = 48). The vertical dotted lines represent the 50% incidence time point as described in the text. The curves were drawn with pooled data from NIEHS and the University of Virginia. The differences among 3 groups were statistically significant (p < 0.001). (b) Kaplan–Meier curves of tumor-free survival of intact ERKO/Wnt-1 animals treated with (n = 24) or without (n = 120) letrozole (20 µg/mouse/day). The difference between these curves was marginally significant (p = 0.055).
Figure 4
(a) Kaplan–Meier curves comparing the effect of 240 pg/ml of E2 with or without fulvestrant (ICI) in castrate ERKO/Wnt-1 animals (n = 21). These curves were not statistically significantly different (p = 0.56). (b) Kaplan–Meier curves showing the effect of 17α-OH-E2 on tumor formation in ERKO/Wnt-1 animals receiving 240 pg/ml 17α-OH-E2 (n = 18). The difference between 17α-OH-E2 and 17β-OH-E2 was not statistically significant (p = 0.34). Data on the 240 pg/ml E2 and vehicle doses are reproduced from Figure 2 and are statistically significant (p = 0.0002).
Figure 5
Uterine wet weights in ER+/Wnt-1 (ER+, white bars) and ERKO/Wnt-1 (ER−, black bars) animals. Shown are mean (±SE) weights of the uterus under various conditions. Data from ER-animals (ovx and E2 groups) were pooled from different experiments (n = 48). 17α-E2/ovx: castrate animals receiving 17α-OH-E2 to produce plasma levels of 240 pg/ml (n = 17). Statistical analysis: ER+ groups: (a) compared to intact (n = 6), (b) compared to ovx (n = 3), (c) compared to ovx + E2 (n = 5); ERKO groups: (d) compared to intact (n = 39), (e) compared to ovx (n = 13), (f) compared to ovx + E2 (n = 48) with all p-values less than 0.001.
Figure 6
Diagrammatic representation of effects of an antiestrogen and an aromatase inhibitor on prevention of breast cancer. This model postulates that antiestrogens only block ERα mediated effects on breast cancer whereas the aromatase inhibitors, by inhibiting estrogen synthesis, abrogate both ERα mediated as well as the genotoxic effects of estrogen.
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