Effects of estrogen on breast cancer development: Role of estrogen receptor independent mechanisms.
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.
Yue
Wei
W
Department of Medicine, Division of Endocrinology and Metabolism, University of Virginia Health System, Charlottesville, VA 22908, USA. wy9c@virginia.edu
Wang
Ji-Ping
JP
Li
Yuebai
Y
Fan
Ping
P
Liu
Guijian
G
Zhang
Nan
N
Conaway
Mark
M
Wang
Hongkun
H
Korach
Kenneth S
KS
Bocchinfuso
Wayne
W
Santen
Richard
R
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D049109:Cell Proliferation; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology / Q000633:toxicity*; D004965:Estrogen Antagonists / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000502:physiology*; D005260:Female; D000077267:Fulvestrant; D006801:Humans; D000077289:Letrozole; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009570:Nitriles / Q000494:pharmacology; D010052:Ovariectomy; D014230:Triazoles / Q000494:pharmacology; D051155:Wnt1 Protein / Q000235:genetics
D000970:Antineoplastic Agents; D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D009570:Nitriles; D014230:Triazoles; D051155:Wnt1 Protein; D000077267:Fulvestrant; D004958:Estradiol; D000077289:Letrozole