Abstract P5-05-15: Pregnancy inhibits mammary carcinogenesis by persistently altering the hypothalamic-pituitary axis

Abstract

Abstract Pregnancy, carried to term at an early age, is probably the best natural protection against breast cancer development. The relative life-long breast cancer risk for women that give birth to their first child before the age of 20 years is approximately half that of nulliparous women. In contrast, if a woman undergoes her first full-term pregnancy after the age of 35, her risk for breast cancer is increased even more than nulliparous women. In the current generation many women are career oriented and have children later in life. Universally the average age at first birth is on the rise. It is critical to understand the underlying mechanism of this protective effect of pregnancy against breast cancer to develop novel prevention strategies to reduce the risk of breast cancer without women having to undergo pregnancy early in life. Earlier, we and others have demonstrated that post-pregnancy there were persistent changes in circulating levels of hormones. In order to understand the significance of these systemic changes we determined alterations in the hypothalamic-pituitary axis in parous rats. In particular, we examined the static and dynamic alterations in the hypothalamic-pituitary axis in response to pregnancy. Seven weeks old female Lewis rats were injected with the chemical carcinogen N-methyl-N-nitrosourea (MNU) at a dose of 50mg/kg body weight intraperitoneally. Two weeks post-carcinogen treatment these rats were housed with a male rat. On the observation of the vaginal plug the male was removed from the cage. Once the rats gave birth they nursed the pups for three weeks and were weaned after that period. Mammary tumorigenesis was monitored through weekly palpation for a period of nine months. A subset of rats at 6, 12 and 24 weeks post-weaning were used to study static and dynamic changes in the level of hormones. We investigated the static alterations in the hypothalamic-pituitary axis in response to pregnancy by measuring the levels of thyrotropin releasing hormone (TRH), growth hormone releasing hormone (GHRH), somatostatin (SS), dopamine (DA), growth hormone (GH) and prolactin (PRL). Next we investigated if the dynamic alterations in the hypothalamic-pituitary axis in response to pregnancy. Control and parous animals were subjected to secretogogue treatments (Growth Hormone Related Peptide 6 for GH and Perphenazine for PRL) and the levels of GH and PRL were measured. We also isolated the pituitary and treated them with the secretogogues and measured the levels of GH and PRL. Our data demonstrated that pregnancy resulted in persistent static and dynamic alterations in circulating levels of hormones. Parous rats response to the secretogogues was severely blunted compared to the control nulliparous rats. The levels of TRH, GHRH, GH and PRL were significantly lowered in parous rats while DA and SS levels were higher in nulliparous rats. As expected mammary carcinogenesis was significantly inhibited in parous rats. Overall, these preliminary results suggest that pregnancy induces persistent changes in hypothalamic-pituitary axis, which results in a lowered hormonal promotion environment resulting in inhibition of mammary carcinogenesis. Citation Format: Subramani R, Galvez A, Pedroza D, Lakshmanaswamy R. Pregnancy inhibits mammary carcinogenesis by persistently altering the hypothalamic-pituitary axis [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-05-15.