Pregnancy Inhibits Mammary Carcinogenesis by Persistently Altering the Hypothalamic–Pituitary Axis

SIMPLE SUMMARY: Breast cancer is one of the most frequently diagnosed cancers and it is the second leading cause of cancer-related death in women. Early first full-term pregnancy has been known to reduce the life-time risk of breast cancer. The actual mechanism by which pregnancy reduces the life-time risk of breast cancer is not well understood. It is well established that hormones are vital for a successful full-term pregnancy and they can also influence the risk of breast cancer. The emphasis has been placed mainly on the ovarian hormones estrogen and progesterone. It is also known that hypothalamic and pituitary hormones can impact the breast. In this study, we investigated how pregnancy alters the hypothalamic/pituitary hormones and what effect these hormonal alterations have on the risk of breast cancer development. Our results demonstrate that pregnancy persistently alters the hypothalamic–pituitary hormonal axis leading to the reduction of breast cancer risk. ABSTRACT: Early full-term pregnancy is known to reduce the lifetime risk of breast cancer. Although the phenomenon of parity-induced protection is well-established, the physiological mechanisms involved in this protection are not clear. Earlier reports have shown that pregnancy results in alterations of hormone levels. How pregnancy affects hypothalamic hormones and how the change, if any, influences breast cancer is not well understood. Seven-week-old female Lewis rats were given N-methyl-N-nitrosourea. Two weeks post carcinogen exposure, a set of females were housed with males to generate the parous rats and another set of rats served as the nulliparous controls. Mammary tumorigenesis was assessed for 9 months. Hypothalamic and pituitary levels of hormones were measured at various timepoints. Further, animals were also challenged with growth hormone and prolactin secretagogues to test the effect of pregnancy on the hypothalamic–pituitary hormonal axis. Persistent alterations in the level of growth hormone-releasing hormone, thyrotropin releasing hormone, dopamine, and somatostatin in the hypothalamus of parous animals was observed. Further, we also observed that pregnancy had a significant effect on the pituitary gland and its response to growth hormone and prolactin secretagogues. Our studies using the rodent model system demonstrate that pregnancy could be reducing the risk of breast cancer by persistently altering the hypothalamic–pituitary axis, which could have implications for breast cancers in humans as well.