Immune-deficient animals to study "hormone-dependent" breast and endometrial cancer.
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 transplantation on opposite sides of athymic mice or by the inoculation of different ratios of ER 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 (EnCa101) 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.(ABSTRACT TRUNCATED AT 400 WORDS)
Jordan
V C
VC
Department of Human Oncology, University of Wisconsin Clinical Cancer Center, Madison 53792.
Gottardis
M M
MM
Robinson
S P
SP
Friedl
A
A
D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D004359:Drug Therapy, Combination; D004958:Estradiol / Q000097:blood / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D051379:Mice; D008815:Mice, Inbred Strains; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010052:Ovariectomy; D011960:Receptors, Estrogen / Q000032:analysis; D013629:Tamoxifen / Q000627:therapeutic use*; D014183:Transplantation, Heterologous; D014594:Uterine Neoplasms / Q000188:drug therapy / Q000473:pathology*
D011960:Receptors, Estrogen; D013629:Tamoxifen; D004958:Estradiol