RANKL/RANK control Brca1 mutation-driven mammary tumors

Abstract

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.

Prevention of breast cancer by RANKL/RANK blockade

“…It remains to be seen whether such a prophylactic treatment would also reduce the incidence of ovarian carcinoma driven by BRCA1 or BRCA2 mutations. Lorenzo Galluzzi 1, 2, 3 [3]. These findings demonstrate that blocking RANKL/RANK limits mammary carcinogenesis driven by BRCA1 mutations, at least in mice.…”

“…Josef Penninger's group provides robust genetic and pharmacological evidence in support of the notion that breast cancer developing in the context of BRCA1 or BRCA2 mutations can be prevented by blocking RANKL/RANK signaling [3]. Since a RANKL-targeting monoclonal antibody (i.e., denosumab) is currently approved by the US Food and Drug Administration (FDA) and equivalent agencies worldwide for the treatment of multiple bone conditions and has an exceptional safety record [4,5], these findings may pave the way to a new era of breast cancer prophylaxis, changing the life of millions of women worldwide.…”

“…However, the deletion of Tnfrsf11a not only led to reduced tumor grade in both models, but also delayed tumor onset in the WapCre C model (which can be maintained for long periods, at odds with the Krt5Cre model that succumbs to skin tumors at around 4 months of age). Moreover, whereas all mice lacking Brca1 and Trp53 in mammary progenitor cells (as per WapCre Cdependent recombination) developed breast neoplasms by approximately 7 months of age, ~ 25% of mice lacking Brca1, Trp53 and Tnfrsf11a never developed breast neoplasms [3].…”

“…To this aim, they crossed the strains described here above with Tnfrsf11a fl/fl mice (in which the RANK-coding sequence is floxed), and monitored not only tumor incidence over time, but also biochemical and pathological parameters of developing neoplasms, including markers of DNA damage, proliferation rate and grade [3]. Tumors developing in the absence of RANK manifested similar degrees of DNA damage and proliferation rate as tumors developing in a RANKproficient background.…”

“…At 15 months of age, as many as 82% mice maintained in control conditions (i.e., receiving an irrelevant antibody fragment) manifested preneoplastic breast lesions, while only 7% of mice receiving the RANK-targeting npg First, RANK and RANKL are expressed at high levels only by breast cancers with BRCA1 or BRCA2 mutations, and RANK protein levels exhibit an exquisite correlation with tumor grade in this scenario (in a clinical cohort of ~250 breast cancer patients). Second, common TNFRSF11A polymorphisms that increase RANK expression levels are associated with an increased risk for breast cancer development in women with BRCA1 or BRCA2 mutations (in a large cohort from the Collaborative Oncological Gene-environment Study cumulatively including 23 000 women with breast cancer) [3].…”