Parathyroid hormone-related protein protects against mammary tumor emergence and is associated with monocyte infiltration in ductal carcinoma in situ.
Parathyroid hormone-related protein (PTHrP) is required for mammary gland development and promotes the growth of breast cancer metastases within bone. However, there are conflicting reports of the prognostic significance of its expression in primary breast cancers. To study the role of PTHrP in early breast cancer, the effect of conditional deletion of PTHrP was examined in the context of neu-induced mammary tumorigenesis. Loss of PTHrP resulted in a higher tumor incidence. Transcriptional profiling of the tumors revealed that PTHrP influenced genes relevant to heterotypic cell signaling, including regulators of monocyte recruitment. Immunohistochemical analysis of human breast cancers revealed that PTHrP expression was associated with both HER-2/neu expression and macrophage infiltration in preinvasive ductal carcinoma in situ. The gene expression signature associated with loss of PTHrP expression in vivo correlated with poorer outcome in human breast cancer. Together, these data indicate that loss of PTHrP accelerates mammary tumorigenesis possibly by a non-cell-autonomous tumor suppressor pathway.
Fleming
Nicholas I
NI
Research Division, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
Trivett
Melanie K
MK
George
Joshy
J
Slavin
John L
JL
Murray
William K
WK
Moseley
Jane M
JM
Anderson
Robin L
RL
Thomas
David M
DM
D000818:Animals; D015703:Antigens, CD / Q000276:immunology; D015214:Antigens, Differentiation, Myelomonocytic / Q000276:immunology; D001943:Breast Neoplasms / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D005260:Female; D017353:Gene Deletion; D020869:Gene Expression Profiling; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000556:secondary; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D009000:Monocytes / Q000276:immunology* / Q000473:pathology; D044162:Parathyroid Hormone-Related Protein / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis; D000097382:CD68 Molecule
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D044162:Parathyroid Hormone-Related Protein; D018719:Erb-b2 Receptor Tyrosine Kinases; C067980:CD68 antigen, human; D000097382:CD68 Molecule