ECTS Abstracts (2015) 1 CABSOC1.4

The dark side of bone anabolics? Intermittent PTH modifies the microenvironment to increase skeletal breast cancer metastasis in vivo

Penelope D Ottewell1, Hannah K Brown1, Kerstin Wiegand1, Ning Wang1, Gloria Allocca1, Peter I Croucher2, Colby L Eaton1 & Ingunn Holen1

1University of Sheffield, Sheffield, UK; 2Garvan Institute of Medical Research, Sydney, New South Wales, Australia.

Intermittent administration of parathyroid hormone (PTH) increases bone volume through positive effects on osteoblasts. However, it is not known whether expansion of osteoblastic cell populations also modifies breast tumour growth in bone. We have investigated the effects of PTH pre-treatment on bone and subsequent skeletal colonisation and growth of breast cancer cells in vivo. Twelve-week old female BALB/c nude mice (n=3–8/group) received PBS (control) or rhPTH 1–34 at 40/80 μg/kg per day for 5 days +/− intracardiac injection of DiD-labelled MDA-MB-231-td-tomato-luc2 cells on day 5. Animal cohorts were sacrificed days 5, 7, 10, 15 (bone studies) or weeks 1, 2, or 9 (tumour studies). Bone was assessed by μCT, histology, bone histomorphometry, and measurement of serum bone turnover markers. Tumour growth was monitored by in vivo imaging and bone homing investigated using two-photon microscopy. PTH treated animals had significantly increased numbers of osteoblasts compared with control (27.79 (40 μg/kg PTH) and 24.07 (80 μg/kg PTH) vs 12.42 (PBS) on day 5; P<0.01) and elevated serum P1NP levels ((92.93:40 μg/kg PTH and 89.31:80 μg/kg PTH) vs 30.87 (PBS) day 7; P<0.01), whereas trabecular bone volume, osteoclast numbers and serum TRAP levels were unaffected. These effects were no longer detectable by day 10. Animals receiving tumour cell injections on day 5 of PTH treatment did not have higher number of colonising tumour cells in tibia/femur (90.6 in 80 μg/kg PTH vs 83.8 in PBS, P>0.05), and the number of tumours detected in the long bones was comparable ((1.86:40 μg/kg PTH and 1.5:80 μg/kg PTH) vs 1.29 (PBS), P>0.05). However, PTH caused increased tumour growth in skeletal sites not normally affected in this model, with higher number of tumours in sites outside the hind limbs (5.71:40 μg/kg PTH and 5.25:80 μg/kg PTH vs 2.57 (PBS); P<0.0001 and P<0.001). These results demonstrate that pre-treatment with PTH modifies the microenvironment, leading to increased breast tumour growth in a range of skeletal sites. (covered by UK Home Office licence PPL40/3462).

Disclosure: The authors declared no competing interests. This work was supported by a Cancer Research UK program grant ‘Defining the bone metastasis niche’.

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