Comparative Effects of the Preventive Effect of Pregnancy, Steroidal Hormones, and hCG in the Transcriptomic Profile of the Rat Mammary Gland

Abstract

The response of the mammary gland to specific carcinogenic stimuli depends upon the physiologic state of the mammary tree under the control of the endocrine system. The administration of optimal carcinogenic doses to young and sexually mature virgin rats induces maximal tumorigenic response [1–6]. This period of highest susceptibility of the mammary gland to be transformed by such stimulus represents the “high risk susceptibility window” (HRSW) [7]. The peak of cancer incidence occurring when virgin rats reach the age of 45–55 days and have had at least two ovulatory cycles after vaginal opening [8] represents the response of numerous mammary terminal end buds (TEBs) that are predominantly composed of progenitor mammary stem cells (PMSCs) [2, 9]. Under the stimulus of the first pregnancy, the mammary gland that has not been exposed to a carcinogenic insult during the early phases of the HRSW enters into a “hormonal protection window” (HPW). During this period the hormones of pregnancy will block any future damage caused by carcinogens or endocrine disruptors through the induction of mammary gland differentiation [2, 10]. Completion of pregnancy induces long-lasting structural and genomic changes in the mammary gland of different strains of rats and in mice [11]. These molecular changes ultimately result in a significant reduction in mammary cancer incidence and number of tumors per animal [8, 9, 12–15]. In the absence of pregnancy, various natural and synthetic hormones have been shown to prevent the initiation of mammary cancer when they are administered to young virgin rats during the HRSW prior to the exposure to a carcinogen or an endocrine disruptor. Daily treatment of virgin Sprague–Dawley rats with hCG at the doses of 1, 5, 10, or 100 IU for 21 days significantly reduces adenocarcinoma incidence and number of adenocarcinomas per animal in a dose-dependent manner [10]. Similarly, treatment with 100 IU hCG daily for 5, 10, or 15 days suffices to induce a significant degree of mammary gland differentiation and protection from cancer initiation [16]. The reduction in cancer incidence resulting from hCG treatment is long-lasting, as demonstrated by the persistent reduction in carcinogenic response to administration of DMBA at 21, 42, or 63 days after termination of the hormonal treatment [10, 13].