Target tissue response to estrogen deprivation: Maintenance of function and estrogen receptor dynamics

Date of Award




Degree Name

Doctor of Philosophy (Ph.D.)


Biochemistry and Molecular Biology

First Committee Member

Stephen J. Zimniski, Committee Chair


In the adult female, estrogens play a vital role in the maintenance of reproductive function. Several forms of cancer, particularly those of the breast, have also been shown to respond to estrogens. We undertook these studies, using the female Sprague-Dawley rat as a model, to examine how normal and mammary tumor target tissues respond to estrogen deprivation, both acutely and over the long term. Earlier studies in our laboratory demonstrated that submaximal estrogen deprivation resulted in tumor regression without cessation of the rats' reproductive cycles. We proposed that the compensation--or lack of compensation--for lowered estrogen levels might, at least in part, be due to tissue differences in regulation of estrogen receptor (ER). In these studies, both maintenance of tissue function and differential modulation of tissue ER were investigated. Careful observation of reproductive cycles, ovulation studies, and examination of target tissue morphology revealed that the rats' reproductive tissues can continue to function normally despite periodic estrogen deprivation. As expected, the majority of tumors regressed with similar treatment. However, induction of the tumors in an estrogen-deprived environment had drastic effects on resulting tumor populations, resulting in a greater proportion of hormone-independent tumors with extremely rapid growth rates.Using a unique ER extraction/exchange assay performed on tissue homogenates, we were able to examine not only total ER levels but also the proportion of ER endogenously occupied by estrogen and thus potentially active at a given time. All ER studies were performed on proestrus, the day of the estrogen surge. Rat uteri were found to respond acutely to estrogen deprivation (within 15 minutes) with an increase in the amount of occupied receptor. This was followed by an increase in total ER that was maintained for greater than nine hours, while control ER decreased. Mammary tumors were also found to increase total ER in response to acute estrogen deprivation. However, with prolonged estrogen deprivation, such as that resulting from ovarian ablation, uterine ER actually increased, while no change was observed in tumor ER. Another difference between the two tissues appeared when attempts were made to saturate ER in vivo with exogenous estrogen; a maximum of 80% of uterine ER was available for binding, while 100% of tumor receptor could be saturated. Tumors identified as hormone-dependent had the highest amount of receptor when compared to independent tumors, especially those induced in a low-estrogen environment. However, "independent" tumors were able to respond to estrogen, as demonstrated by upregulation of the protooncogenes c-fos and c-myc. Therefore, while estrogens are important in the function of many tissues, the response of these tissues to estrogen deprivation is complex, varying over time and differing from one tissue to another.


Biology, Molecular; Health Sciences, Obstetrics and Gynecology; Health Sciences, Medicine and Surgery

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