RANKL/RANK control Brca1 mutation-driven mammary tumors

Breast cancer is the most common female cancer, affecting approximately one in eight women during their life-time. Besides environmental triggers and hormones, inherited mutations in the breast cancer 1 (BRCA1) or BRCA2 genes markedly increase the risk for the development of breast cancer. Here, using two different mouse models, we show that genetic inactivation of the key osteoclast differentiation factor RANK in the mammary epithelium markedly delayed onset, reduced incidence, and attenuated progression of Brca1;p53 mutation-driven mammary cancer. Long-term pharmacological inhibition of the RANK ligand RANKL in mice abolished the occurrence of Brca1 mutation-driven pre-neoplastic lesions. Mechanistically, genetic inactivation of Rank or RANKL/RANK blockade impaired proliferation and expansion of both murine Brca1;p53 mutant mammary stem cells and mammary progenitors from human BRCA1 mutation carriers. In addition, genome variations within the RANK locus were significantly associated with risk of developing breast cancer in women with BRCA1 mutations. Thus, RANKL/RANK control progenitor cell expansion and tumorigenesis in inherited breast cancer. These results present a viable strategy for the possible prevention of breast cancer in BRCA1 mutant patients

Neonatal immunology: responses to pathogenic microorganisms and epigenetics reveal an “immunodiverse” developmental state

Neonatal animals have heightened susceptibility to infectious agents and are at increased risk for the development of allergic diseases, such as asthma. Experimental studies using animal models have been quite useful for beginning to identify the cellular and molecular mechanisms underlying these sensitivities. In particular, results from murine neonatal models indicate that developmental regulation of multiple immune cell types contributes to the typically poor responses of neonates to pathogenic microorganisms. Surprisingly, however, animal studies have also revealed that responses at mucosal surfaces in early life may be protective against primary or secondary disease. Our understanding of the molecular events underlying these processes is less well developed. Emerging evidence indicates that the functional properties of neonatal immune cells and the subsequent maturation of the immune system in ontogeny may be regulated by epigenetic phenomena. Here, we review recent findings from our group and others describing cellular responses to infection and developmentally regulated epigenetic processes in the newborn