Parathyroid hormone-related protein (
PTHrP) is a key component in breast development and breast tumour biology.
PTHrP has been discovered as a causative agent of hypercalcaemia of
malignancy and is also one of the main factors implicated in
breast cancer mediated
osteolysis. Clinical studies have determined that
PTHrP expression by primary breast
cancers was an independent predictor of improved prognosis. Furthermore,
PTHrP has been demonstrated to cause tumour cell death both in vitro and in vivo. Apo2L/TRAIL is a promising new anti-
cancer agent, due to its ability to selectively induce apoptosis in
cancer cells whilst sparing most normal cells. However, some
cancer cells are resistant to Apo2L/TRAIL-induced apoptosis thus limiting its therapeutic efficacy. The effects of
PTHrP on cell death signalling pathways initiated by Apo2L/TRAIL were investigated in
breast cancer cells. Expression of
PTHrP in Apo2L/TRAIL resistant cell line MCF-7 sensitised these cells to Apo2L/TRAIL-induced apoptosis. The actions of
PTHrP resulted from intracellular effects, since exogenous treatment of
PTHrP had no effect on Apo2L/TRAIL-induced apoptosis. Apo2L/TRAIL-induced apoptosis in
PTHrP expressing cells occurred through the activation of
caspase-10 resulting in
caspase-9 activation and induction of apoptosis through the
effector caspases,
caspase-6 and -7.
PTHrP increased cell surface expression of Apo2L/TRAIL
death receptors, TRAIL-R1 and TRAIL-R2. Antagonistic
antibodies against the
death receptors demonstrated that Apo2L/TRAIL mediated its apoptotic signals through activation of the TRAIL-R2 in
PTHrP expressing
breast cancer cells. These studies reveal a novel role for
PTHrP with Apo2L/TRAIL that maybe important for future diagnosis and treatment of
breast cancer.