Adrenal Regulation of Mammary Tumorigenesis in Female Sprague-Dawley Rats: Incidence, Latency, and Yield of Mammary Tumors

Abstract

Huggins and Morii (J. Exp. Med., 114: 741, 1961) reported that massive adrenal necrosis occurs in 79 and 100% of female Sprague-Dawley rats receiving 20 and 30 mg, respectively, of the mammary carcinogen 7,12-dimethylbenz(a)anthracene (DMBA). Here, adrenal necrosis and regeneration were studied in 158 rats for up to 21 days post-DMBA by radioautography of the adrenals of animals given 50 µCi [³H]thymidine 30 min before sacrifice. Adrenal cell proliferation was markedly inhibited 21 days post-DMBA. Regenerated adrenals were more susceptible to this adrenocorticolytic effect. To investigate if alterations in adrenal function modify tumorigenesis, animals underwent adrenalectomies (ADX), hypophysectomies, ovariectomies, and pituitary transplants alone or in combination 6 days after receiving DMBA (20 mg/100 g intragastrically) at 50 days of age. To prevent adrenal necrosis, 24 animals were pretreated with metyrapone. Methylprednisolone acetate, 1 mg i.m., was given to 40 animals every 5 days beginning 6 days post-DMBA. There were 50 non-DMBA-treated intact and surgical controls. DMBA was necessary but not sufficient to induce mammary tumors. No tumors developed in controls or in 46 animals hypophysectomized 6 days after DMBA. Metyrapone reduced tumor incidence and yield. ADX after DMBA treatment increased the tumorigenic response and eliminated resistance to tumorigenesis in older rats. Only three tumors developed in DMBA-treated rats receiving methylprednisolone acetate. Mammary tumorigenesis was increased by pituitary transplant 6 days after DMBA to intact and ADX animals. Ovariectomy 6 days after DMBA was as effective as methylprednisolone acetate in preventing tumorigenesis; ADX did not overcome either inhibition. We conclude that adrenal hormones inhibit proliferation of initiated mammary cells.