p53 expression in breast and endometrium during estrogen and tamoxifen treatment of surgically postmenopausal cynomolgus macaques.
Estrogens are important for both normal cell growth and malignant proliferation in the mammary gland as well as in the endometrium. Tamoxifen is a non-steroidal anti-estrogen widely used in breast cancer treatment. In recent years reports have been made of an increased risk of endometrial carcinoma during tamoxifen treatment. We used surgically menopausal cynomolgus macaques to study proliferation and p53 expression during hormonal replacement therapy (HRT) and tamoxifen treatment. Animals were treated continuously for 35 months with either conjugated equine estrogens (CEE; n = 20); medroxyprogesterone acetate (MPA; n = 17); the combination of CEE + MPA (n = 13); or tamoxifen (n = 17) for 35 months. We found an increased expression of p53 in normal breast and endometrial tissue linked to CEE but not tamoxifen treatment. In the breast alveoli there was an association between proliferation measured by morphometry and p53 expression in all groups. However, in the endometrium CEE induced significantly more p53 positivity than tamoxifen, 9/20 vs. 3/17 in glands and 9/19 vs. 0/17 in stroma, respectively. If indeed long-term treatment with tamoxifen as in the present study could inactivate the tumor-suppressive function of p53, endometrial cells might thereby become more susceptible to genetic lesions associated with carcinogenesis.
Isaksson
E
E
Department of Oncology, Radiumhemmet, Karolinska Hospital, Stockholm, Sweden.
Cline
J M
JM
Skoog
L
L
Söderqvist
G
G
Wilking
N
N
von Schoultz
E
E
von Schoultz
B
B
D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D004717:Endometrium / Q000187:drug effects*; D015914:Estrogen Replacement Therapy; D004966:Estrogens, Conjugated (USP) / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000096:biosynthesis / Q000235:genetics; D008252:Macaca fascicularis; D008297:Male; D008321:Mammary Glands, Animal / Q000187:drug effects*; D017258:Medroxyprogesterone Acetate / Q000494:pharmacology; D013629:Tamoxifen / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis* / Q000235:genetics
D018931:Antineoplastic Agents, Hormonal; D004966:Estrogens, Conjugated (USP); D019394:Ki-67 Antigen; D016159:Tumor Suppressor Protein p53; D013629:Tamoxifen; D017258:Medroxyprogesterone Acetate