Functional variant of KLOTHO: a breast cancer risk modifier among BRCA1 mutation carriers of Ashkenazi origin

Abstract

Klotho is a transmembrane protein that can be shed and act as a circulating hormone and is a putative tumor suppressor in breast cancer. A functional variant of KLOTHO (KL-VS) contains two amino acid substitutions F352V and C370S and shows reduced activity. Germ-line mutations in BRCA1 and BRCA2 substantially increase lifetime risk of breast and ovarian cancers. Yet, penetrance of deleterious BRCA1 and BRCA2 mutations is incomplete even among carriers of identical mutations. We examined the association between KL-VS and cancer risk among 1115 Ashkenazi Jewish women: 236 noncarriers, 631 BRCA1 (185delAG, 5382insC) carriers and 248 BRCA2 (6174delT) carriers. Among BRCA1 carriers, heterozygosity for the KL-VS allele was associated with increased breast and ovarian cancer risk (hazard ratio 1.40, 95% confidence intervals 1.08-1.83, P ¼ 0.01) and younger age at breast cancer diagnosis (median age 48 vs 43 P ¼ 0.04). KLOTHO and BRCA2 are located on 13q12, and we identified linkage disequilibrium between KL-VS and BRCA2 6174delT mutation. Studies in breast cancer cells showed reduced growth inhibitory activity and reduced secretion of klotho F352V compared with wildtype klotho. These data suggest KL-VS as a breast and ovarian cancer risk modifier among BRCA1 mutation carriers. If validated in additional cohorts, the presence of KL-VS may serve as a predictor of cancer risk among BRCA1 mutation carriers.

Klotho Inhibits Transforming Growth Factor-β1 (TGF-β1) Signaling and Suppresses Renal Fibrosis and Cancer Metastasis in Mice

“…These findings coincide with the fact that Klotho counteracts EMT, and imply that adverse effects of decreased Klotho on cancer may be enhanced in a population with accelerated cancer initiation. In fact, a functional variation of Klotho (F352V/C370S) that exhibits reduced secretion in in vitro experiments (44) is associated with increased risk for breast and ovarian cancer as well as with younger age at diagnosis among BRCA1 mutation carriers (45). Because inhibition of IGF-1 receptor suppresses breast cancer (46), these observations have been explained by the ability of Klotho to suppress IGF-1 signaling (1,17).…”

Promoter methylation and age-related downregulation of Klotho in rhesus monkey

“…Changes in KL gene expression would, over time, impact normal function of all downstream pathways. Evidence of such an effect is observed in the KL polymorphism KL VS (Arking et al 2002) where slight changes in KL function increases risk of disease (Arking et al 2002(Arking et al , 2003(Arking et al , 2005Invidia et al 2010;Wolf et al 2010). Of course, the overall contribution of a small change in one gene would not induce a dramatic phenotype in humans as it does in the KL knockout mouse; however, small changes in KL and numerous other genes would add up over time.…”

KL1 Internal Repeat Mediates Klotho Tumor Suppressor Activities and Inhibits bFGF and IGF-I Signaling in Pancreatic Cancer

“…We noted high klotho expression in normal breast tissue and low klotho expression in breast cancer and discovered that overexpression of klotho specifically inhibited growth of breast cancer cells in vitro (12). We also discovered that a less active functional variant of KLOTHO, which contains 2 amino acid substitutions F352V and C370S (KL-VS), is associated with increased breast cancer risk among BRCA1 mutation carriers (20).…”

“…S2). Genetic analysis (data not shown) revealed that while wild-type klotho gene was found in MiaPaCa2 and Colo357, only the less active klotho variant, KL-VS (20), was detected in Panc1.…”