Project Summary The mitochondrial enzyme sirtuin 4 (SIRT4) is downregulated in breast cancer tissue, but the reason for this is not clear. In order to elucidate this, we first sought to determine the role of SIRT4 in normal mammary tissue. We have discovered that SIRT4 is critical for ensuring normal mammary development. In mice with a total lack of SIRT4 (SIRT4KO mice), mammary glands do not fully develop during puberty. As a result, they do not produce enough maternal breast milk during pregnancy and nearly 100% of their young perish two days after birth. We now seek to uncover the mechanism by which SIRT4 influences mammary gland development. First, we seek to investigate the potential role of the ovarian hormones 17β-estradiol (E2) and progesterone (P4) in mediating the effects of SIRT4 on mammary development (Aim 1). These two hormones are essential for initiating growth of milk-producing mammary ducts during puberty and pregnancy and the mammary defects seen in SIRT4KO mice are reminiscent of the defects seen in mice with disrupted E2 or P4 signaling. Furthermore, since SIRT4 is found in mitochondria and is known to have many metabolic effects, we seek to investigate the possibility that SIRT4 regulates mammary development by controlling nutrient metabolism in mammary glands (Aim 2). Altered metabolic states in both mice and humans have been shown to inhibit mammary development. For example, both underweight and overweight mice have impaired mammary development that can result in insufficient lactation. Thus, we seek to determine whether the known effects of SIRT4 on nutrient metabolism may contribute to how SIRT4 regulates mammary development. Overall, our proposed studies will reveal a new role for SIRT4 in regulating mammary development. Ultimately, by investigating how SIRT4 influences normal mammary physiology, we may better understand why SIRT4 expression levels are downregulated in breast cancer tissue and whether this contributes to disease progression.

Project Narrative This project aims to better understand how the mitochondrial enzyme sirtuin 4 (SIRT4) controls mammary gland development. We have discovered that mice with a loss of SIRT4 (SIRT4KO mice) have underdeveloped mammary glands such that they are unable to produce enough maternal breast milk to support their young; however, the mechanism behind this defect is unknown. We propose to further characterize the mammary defects in SIRT4KO mice and identify the primary developmental pathways affected by SIRT4.