Peroral Estradiol Is Sufficient to Induce Carcinogen-Induced Mammary Tumorigenesis in Ovariectomized Rats without Progesterone.
A role for estrogens in breast cancer is widely accepted, however, recent evidence highlights that timing and exposure levels are important in determining whether they elicit harmful versus beneficial effects. The rat chemical carcinogen model has been widely used to study the effects of estrogens but conclusions on the levels that lead to tumor development and an absolute requirement for progesterone (P4) are lacking. A newer method of hormone administration mixes hormones with nut butter for peroral consumption allowing for a less stressful method of long-term administration with lower spikes in serum estradiol (E2) levels. The present study was designed to determine if estrogens alone at a physiological dose can drive carcinogen-induced tumors in ovariectomized (OVX) rats or if P4 is also required using this method of hormone administration. Short-term studies were conducted to determine the dose of estrogen (E) that would lead to increased uterine weight following OVX. Subsequently, rats were OVX on postnatal day (PND) 40 then treated daily with E (600 μg/kg/day), P4 (15 mg/kg/day), or the combination. On PND 50, all rats were injected with nitrosomethylurea to induce mammary tumors. Uterine weights, body weights, and serum E2 levels were measured to demonstrate the efficacy of the method for increasing E2 levels during long-term treatment. After 26 weeks, tumor incidence was similar in Sham, E, and E + P4 animals indicating that E was sufficient to induce tumorigenesis when hormone levels were normalized by this method. This study demonstrates peroral administration can be used in long-term studies to elucidate relationships between different types and levels of steroid hormones.
Department of Animal Science, Rutgers, The State University of New Jersey, New Brunswick, NJ, United States of America.
Hillary
H
Stires
Department of Animal Science, Rutgers, The State University of New Jersey, New Brunswick, NJ, United States of America.
Mariana
M
Saboya
Department of Animal Science, Rutgers, The State University of New Jersey, New Brunswick, NJ, United States of America.
Samantha P
SP
Globerman
Department of Animal Science, Rutgers, The State University of New Jersey, New Brunswick, NJ, United States of America.
Wendie S
WS
Cohick
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D063646:Carcinogenesis / Q000139:chemically induced / Q000187:drug effects / Q000473:pathology*; D002273:Carcinogens / Q000633:toxicity*; D049109:Cell Proliferation / Q000187:drug effects; D004958:Estradiol / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood; D005260:Female; D007150:Immunohistochemistry; D015674:Mammary Neoplasms, Animal / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced* / Q000473:pathology*; D008770:Methylnitrosourea; D009929:Organ Size / Q000187:drug effects; D010052:Ovariectomy; D011374:Progesterone / Q000009:adverse effects*; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014599:Uterus / Q000187:drug effects / Q000473:pathology
D002273:Carcinogens; D011374:Progesterone; D004958:Estradiol; D008770:Methylnitrosourea