Tanya Vaughan

Association of A vitamin D receptor polymorphism with sporadic breast cancer development.

Breast cancer is the leading cause of cancer death among Australian women and its incidence is annually increasing. Genetic factors are involved in the complex etiology of breast cancer. The seco‐steroid hormone, 1,25 dihydroxy vitamin D3 can influence breast cancer cell growth in vitro. A number of studies have reported correlations between vitamin D receptor (VDR) gene polymorphisms and several diseases including prostate cancer and osteoporosis. In breast cancer, low vitamin D levels in serum are correlated with disease progression and bone metastases, a situation also noted in prostate cancer and suggesting the involvement of the VDR. In our study, 2 restriction fragment length polymorphisms (RFLP) in the 3′ region (detected by Apa1 and Taq1) and an initiation codon variant in the 5′ end of the VDR gene (detected by Fok1) were tested for association with breast cancer risk in 135 females with sporadic breast cancer and 110 cancer‐free female controls. Allele frequencies of the 3′ ApaI polymorphism showed a significant association (p = 0.016; OR = 1.56, 95% CI = 1.09–2.24) while the TaqI RFLP showed a similar trend (p = 0.053; OR = 1.45, 95% CI = 1.00–2.00). Allele frequencies of the FokI polymorphism were not significantly different (p = 0.97; OR = 0.99, 95% CI = 0.69–1.43) in the study population. Our results suggest that specific alleles of the VDR gene located near the 3′ region may identify an increased risk for breast cancer and justify further investigation of the role of VDR in breast cancer. Int. J. Cancer 83:723–726, 1999.

Vitamin D receptor genotypes influence the success of calcitriol therapy for recurrent vertebral fracture in osteoporosis.

Osteoporosis is a complex multi-factorial disease where environment, diet and genetics play a role in determining susceptibility. Patients with existing vertebral fracture have a heightened risk of further recurrent vertebral fracture. The efficacy of new osteoporosis therapies is often compared to calcium supplementation. 1,25-dihydroxyvitamin D3 (calcitriol) acts through the vitamin D receptor (VDR) and is effective at reducing recurrent vertebral fracture risk. Because the VDR controls calcium metabolism, we hypothesized that genetic variation at the VDR locus may influence response to both calcium and calcitriol therapy. Postmenopausal women with osteoporosis from a 3-year study comparing calcitriol versus calcium for prevention of vertebral fractures were genotyped for VDR alleles detected by FokI, BsmI, ApaI and TaqI. Data were analysed by hierarchical log-linear analysis and robust analysis of variance for relationships to fracture outcomes. Significant differences in the vertebral fracture rate in response to calcium therapy were observed between VDR genotypes (P<0.001). Calcium appeared to be equally effective as calcitriol in particular genotypes. The response to calcitriol therapy was most pronounced in patients carrying the TaqI t allele in combination with the FokI f initiation codon variant: f+t+ carriers were 11.3-fold less likely to sustain recurrent vertebral fracture in the last 2 years of the trial while on calcitriol therapy compared to calcium (P=1.4×10−5). Response to both calcium and calcitriol therapy is dependent on genetic variation at the VDR locus and two loci in the VDR gene may contribute to this effect.

Over-expression of TBP-2, a protein involved in redox regulation, inhibits osteoclastogenesis.

Using gene array analysis, we found that thioredoxin (TRX) binding protein-2 (TBP-2) was down-regulated during osteoclast (OC) differentiation. TBP-2 is a negative regulator of TRX, a small protein with a redox-active dithiol active site. TRX enhances DNA binding of redox-sensitve transcription factors such as NF?B and AP-1. OC were generated on dentine slices using human CFU-GM precursor cells treated with RANKL and M-CSF. At 4 days of culture, efficient (>80%) infection with adenovirus expressing galactosidase (AdLacZ) was achieved. Infection with adenovirus expressing TBP-2 (AdTBP-2) for 14 days resulted in 66% reduction in the total TRAP+ area and 50% reduction in OC numbers as compared to the AdLacZ control. The size of OC formed in the presence of AdTBP-2 was reduced by 66% and they contained fewer nuclei. Resorption of dentine was inhibited by 80%. In mature OC infected with AdTBP-2, RANKL-induced NF?B activation was reduced by 63% and Western analysis demonstrated markedly increased expression of TBP-2 protein. We have shown that the over-expression of TBP-2, a gene down-regulated during OC formation, inhibits OC differentiation and NF?B activation. These results are consistent with the known function of TBP-2 as a negative regulator of TRX and the importance of the redox-sensitive transcription factor NF?B in osteoclastogenesis.It has been postulated that muscle and bone form an operational unit; that is, factors that affect muscle will also influence bone. It also is thought that muscle action is paramount in affecting bone adaptation; if so, then it would be expected that muscle development (or lean tissue as a surrogate of muscle) during the growing years should precede bone mineral accrual. We have shown previously that this is the case for total body mass; however, in theory this relationship should be even stronger at the extremities where muscle action is more isolated. The purpose of this study was to investigate the relationship of the timing of bone-free peak lean mass accrual (PLM) to peak bone mineral mass accrual (PBM) at the arms and legs. Subjects (70 boys and 67 girls) were measured annually (DXA: Hologic 2000 QDR in array mode). Whole year velocity values were calculated for bone-free lean tissue and bone mineral content. The mean age of peak tissue accrual was then calculated as the mean of the peak. Dependent t-tests were done to test for differences between the age of PLM and PBM (p<.05). As shown in the following table, PLM occurred prior to PBM at both sites in both boys and girls; however, this difference was not statistically significant at the legs in girls. These preliminary data support the hypotheses that PLM (a surrogate measure for muscle mass) precedes PBM and that muscle and bone development are closely related.