TY - JOUR
T1 - Immune-deficient animals to study "hormone-dependent" breast and endometrial cancer
AU - Jordan, V. Craig
AU - Gottardis, M. M.
AU - Robinson, S. P.
AU - Friedl, A.
N1 - Funding Information:
Acknowledgements-A.F. was a recipiento f a scholarship from the DeutscheF orschungsgemeinschtaoft a llow him to work at theW isconsinC linical CancerC enter.W e especially wish to thankD r D. Buchlerf or her assistancein obtaining tumor BR, BRMet and Dr E. Borden and Randy Wagner for providing the facilitiest o conductt he NK cell assays. These studiesw ere supportedi n part by NIH grant POl-20432P, 30 CA 20432M. .M.G. was supportedb y Human Cancer Biology trainingg rant NC1 T32 CA09471.
PY - 1989
Y1 - 1989
N2 - Athymic (nu/nu) mice are T cell deficient and can accept xenografts of human tumor material. Hormone-dependent tumor growth can be demonstrated in ovariectomized athymic mice by estrogen administration. Estrogen receptor (ER) positive MCF-7 breast cancer cells implanted into the axillary mammary fat do not grow into palpable tumors unless sustained release preparations of estrogen are administered. The non-steroidal antiestrogen tamoxifen, though it exhibits estrogenic properties in the mouse, does not facilitate MCF-7 tumor growth (during short term, i.e. 8 weeks of therapy) and can prevent estradiol-stimulated growth. In contrast, ER negative MDA-MB-231 cells grow with or without estrogen administration and tamoxifen does not control tumor growth. These statements reflect current dogma concerning the value of athymic mice to confirm the hormone dependent growth of cancer cells in vivo. Our aim has been to define the limits of this dogma and to investigate the growth relationship of hormone-dependent and independent cells with their host environment. The potential endocrine or paracine effect of ER negative tumors on the growth of ER positive tumors was evaluated by transplanatation on opposite sides of athymic mice or by the inoculation of different ratiosofER positive/negative cells (MCF-7: MDA-MB-231 9:1,99:1,999:1). MCF-7 cells could not be encouraged to grow by a rapidly growing MDA-MB-231 tumor on the opposite side of the animal. Similarly ER negative tumors grew out of the mixed tumor inoculates suggesting that ER positive tumors could not be encouraged to grow preferentially by the paracrine influences of ER negative cells. However, estrogen facilitates the growth of an ER positive tumor following inoculation of mixed cell populations. Antiestrogen treatment can blunt estrogen-stimulated growth but cannot control the growth of ER positive/negative containing tumors. ER positive endometrial tumors grow in response to estrogen treatment and some (EnCalOl) have been shown to grow in response to tamoxifen or a combination of tamoxifen and estrogen. More unusual though is our recent observation that an ER negative primary endometrial tumor (BR) and its metastasis (BR-MET) grow more rapidly in estrogen-treated athymic mice. This finding seems to have far-ranging consequences for our view of hormone-dependent growth. Either our view of estrogen-stimulated growth needs to be modified or the host is specifically altered during estrogen treatment. We have taken the position that since natural killer cells (present in athymic mice) can be lowered by estrogen this may result in an increased tumor cell survival in the heterotransplant model. Tumors would therefore appear to grow more rapidly in the estrogen-rich environment. To test this hypothesis we have used beige (NK cell deficient) mice to compare the growth characteristics of tumor BR with and without estrogen. Unlike the athymic mouse where estrogen facilitates the growth of tumor Br, estrogen had no effect in beige mice. These findings not only point to the importance of defining models to evaluate hormone dependency in vivo but also provide a potential insight into the relationship between the tumor and its host environment.
AB - Athymic (nu/nu) mice are T cell deficient and can accept xenografts of human tumor material. Hormone-dependent tumor growth can be demonstrated in ovariectomized athymic mice by estrogen administration. Estrogen receptor (ER) positive MCF-7 breast cancer cells implanted into the axillary mammary fat do not grow into palpable tumors unless sustained release preparations of estrogen are administered. The non-steroidal antiestrogen tamoxifen, though it exhibits estrogenic properties in the mouse, does not facilitate MCF-7 tumor growth (during short term, i.e. 8 weeks of therapy) and can prevent estradiol-stimulated growth. In contrast, ER negative MDA-MB-231 cells grow with or without estrogen administration and tamoxifen does not control tumor growth. These statements reflect current dogma concerning the value of athymic mice to confirm the hormone dependent growth of cancer cells in vivo. Our aim has been to define the limits of this dogma and to investigate the growth relationship of hormone-dependent and independent cells with their host environment. The potential endocrine or paracine effect of ER negative tumors on the growth of ER positive tumors was evaluated by transplanatation on opposite sides of athymic mice or by the inoculation of different ratiosofER positive/negative cells (MCF-7: MDA-MB-231 9:1,99:1,999:1). MCF-7 cells could not be encouraged to grow by a rapidly growing MDA-MB-231 tumor on the opposite side of the animal. Similarly ER negative tumors grew out of the mixed tumor inoculates suggesting that ER positive tumors could not be encouraged to grow preferentially by the paracrine influences of ER negative cells. However, estrogen facilitates the growth of an ER positive tumor following inoculation of mixed cell populations. Antiestrogen treatment can blunt estrogen-stimulated growth but cannot control the growth of ER positive/negative containing tumors. ER positive endometrial tumors grow in response to estrogen treatment and some (EnCalOl) have been shown to grow in response to tamoxifen or a combination of tamoxifen and estrogen. More unusual though is our recent observation that an ER negative primary endometrial tumor (BR) and its metastasis (BR-MET) grow more rapidly in estrogen-treated athymic mice. This finding seems to have far-ranging consequences for our view of hormone-dependent growth. Either our view of estrogen-stimulated growth needs to be modified or the host is specifically altered during estrogen treatment. We have taken the position that since natural killer cells (present in athymic mice) can be lowered by estrogen this may result in an increased tumor cell survival in the heterotransplant model. Tumors would therefore appear to grow more rapidly in the estrogen-rich environment. To test this hypothesis we have used beige (NK cell deficient) mice to compare the growth characteristics of tumor BR with and without estrogen. Unlike the athymic mouse where estrogen facilitates the growth of tumor Br, estrogen had no effect in beige mice. These findings not only point to the importance of defining models to evaluate hormone dependency in vivo but also provide a potential insight into the relationship between the tumor and its host environment.
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U2 - 10.1016/0022-4731(89)90079-4
DO - 10.1016/0022-4731(89)90079-4
M3 - Article
C2 - 2626014
AN - SCOPUS:0024817495
SN - 0022-4731
VL - 34
SP - 169
EP - 176
JO - Journal of Steroid Biochemistry
JF - Journal of Steroid Biochemistry
IS - 1-6
ER -