Am J Cancer Res 2013;3(5): 500-508
Original Article
Enhancement of taxol, doxorubicin and zoledronate anti-proliferation action on
triple-negative breast cancer cells by a PTHrP blocking monoclonal antibody
Anne Camirand, Ibtihal Fadhil, Aimée-Lee Luco, Benoît Ochietti, Richard B Kremer
Department of Medicine, McGill University Health Centre, Montréal, QC Canada, H3A 1A1
Received September 12, 2013; Accepted October 7, 2013; Epub November 1, 2013; Published November 15, 2013
Abstract: Triple-negative breast cancers (TNBCs) are heterogeneous cancers that present tumors without the estrogen receptor
(ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Because of the absence of these
receptors, there are currently no known specific molecular targets for treatment, and although TNBC tumors are chemosensitive,
prognosis is poor because this type of cancer relapses more frequently and more aggressively than hormone receptor-positive
cancers. The mechanisms by which TNBCs escape control by chemotherapy are not clear, and it is crucial to identify novel
molecular drivers that can be targeted in order to develop more efficient therapeutic approaches. We recently highlighted a
pleiotropic role for parathyroid hormone-related protein (PTHrP) in all stages of breast cancer, and used our neutralizing
anti-PTHrP monoclonal antibody (mAb M158) to efficiently inhibit progression and metastasis of human breast cancer xenografts
in athymic mice. In the present study, we present evidence for a strong in vitro anti-proliferative effect of our blocking anti-PTHrP
mAb M158 as a single agent on TNBC lines of various subtypes that are known to express PTHrP (MDA-MB-231, BT-549,
MDA-MB-435). The same mAb is inactive in a TNBC line without detectable PTHrP expression (MDA-MB-468). In in vitro
combination studies, the mAb enhances the effect of the chemotherapeutic drugs taxol and doxorubicin in PTHrP-positive TNBC
cells in an additive manner. When combined with the bisphosphonate zoledronate, M158 can act in additive or antagonistic
fashion in vitro depending on the cell line. Our observations identify PTHrP as a novel target against TNBC cell proliferation, and
suggest that combination therapies that include an anti-PTHrP approach might increase treatment efficacy in patients with
PTHrP-positive TNBC. (ajcr0000229).
Keywords: Breast cancer cell lines, PTHrP, TNBC, zoledronate, doxorubicin, paclitaxel, neutralizing antibody
Address correspondence to: Dr. Richard B Kremer, Department of Medicine, Calcium Research Lab., Royal Victoria Hospital,
Rm. H4.67 687 ouest Avenue des Pins, Montréal, Québec, Canada, H3A 1A1. Tel: 514-843-1632; Fax: 514-843-1712; E-mail:
richard.kremer@mcgill.ca
Original Article
Enhancement of taxol, doxorubicin and zoledronate anti-proliferation action on
triple-negative breast cancer cells by a PTHrP blocking monoclonal antibody
Anne Camirand, Ibtihal Fadhil, Aimée-Lee Luco, Benoît Ochietti, Richard B Kremer
Department of Medicine, McGill University Health Centre, Montréal, QC Canada, H3A 1A1
Received September 12, 2013; Accepted October 7, 2013; Epub November 1, 2013; Published November 15, 2013
Abstract: Triple-negative breast cancers (TNBCs) are heterogeneous cancers that present tumors without the estrogen receptor
(ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Because of the absence of these
receptors, there are currently no known specific molecular targets for treatment, and although TNBC tumors are chemosensitive,
prognosis is poor because this type of cancer relapses more frequently and more aggressively than hormone receptor-positive
cancers. The mechanisms by which TNBCs escape control by chemotherapy are not clear, and it is crucial to identify novel
molecular drivers that can be targeted in order to develop more efficient therapeutic approaches. We recently highlighted a
pleiotropic role for parathyroid hormone-related protein (PTHrP) in all stages of breast cancer, and used our neutralizing
anti-PTHrP monoclonal antibody (mAb M158) to efficiently inhibit progression and metastasis of human breast cancer xenografts
in athymic mice. In the present study, we present evidence for a strong in vitro anti-proliferative effect of our blocking anti-PTHrP
mAb M158 as a single agent on TNBC lines of various subtypes that are known to express PTHrP (MDA-MB-231, BT-549,
MDA-MB-435). The same mAb is inactive in a TNBC line without detectable PTHrP expression (MDA-MB-468). In in vitro
combination studies, the mAb enhances the effect of the chemotherapeutic drugs taxol and doxorubicin in PTHrP-positive TNBC
cells in an additive manner. When combined with the bisphosphonate zoledronate, M158 can act in additive or antagonistic
fashion in vitro depending on the cell line. Our observations identify PTHrP as a novel target against TNBC cell proliferation, and
suggest that combination therapies that include an anti-PTHrP approach might increase treatment efficacy in patients with
PTHrP-positive TNBC. (ajcr0000229).
Keywords: Breast cancer cell lines, PTHrP, TNBC, zoledronate, doxorubicin, paclitaxel, neutralizing antibody
Address correspondence to: Dr. Richard B Kremer, Department of Medicine, Calcium Research Lab., Royal Victoria Hospital,
Rm. H4.67 687 ouest Avenue des Pins, Montréal, Québec, Canada, H3A 1A1. Tel: 514-843-1632; Fax: 514-843-1712; E-mail:
richard.kremer@mcgill.ca
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American Journal of Cancer Research
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