The internally truncated LRP5 receptor presents a therapeutic target in breast cancer.
BACKGROUND
Breast cancer is a common malignant disease, which may be caused by a number of genes deregulated by genomic or epigenomic events. Deregulated WNT/beta-catenin signaling with accumulation of beta-catenin is common in breast tumors, but mutations in WNT signaling pathway components have been rare. An aberrantly spliced internally truncated LRP5 receptor (LRP5Delta666-809, LRP5Delta) was shown recently to be resistant to DKK1 inhibition, and was required for beta-catenin accumulation in hyperparathyroid tumors and parathyroid tumor growth.


RESULTS
Here we show, by reverse transcription PCR and Western blot analysis, that LRP5Delta is frequently expressed in breast tumors of different cancer stage (58-100%), including carcinoma in situ and metastatic carcinoma. LRP5Delta was required in MCF7 breast cancer cells for the non-phosphorylated active beta-catenin level, transcription activity of beta-catenin, cell growth in vitro, and breast tumor growth in a xenograft SCID mouse model. WNT3 ligand, but not WNT1 and WNT3A augmented the endogenous beta-catenin activity of MCF7 cells in a DKK1-insensitive manner. Furthermore, an anti-LRP5 antibody attenuated beta-catenin activity, inhibited cell growth, and induced apoptosis in LRP5Delta-positive MCF7 and T-47D breast cancer cells, but not in control cells.


CONCLUSIONS
Our results suggest that the LRP5Delta receptor is strongly implicated in mammary gland tumorigenesis and that its aberrant expression present an early event during disease progression. LRP5 antibody therapy may have a significant role in the treatment of breast cancer.
Björklund
Peyman
P
Department of Surgical Sciences, Endocrine Unit, Uppsala University, Uppsala University Hospital, Uppsala, Sweden.
Svedlund
Jessica
J
Olsson
Anna-Karin
AK
Akerström
Göran
G
Westin
Gunnar
G
D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000628:therapy*; D002277:Carcinoma / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D011973:Receptors, LDL / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism; D060508:Wnt3 Protein; D060509:Wnt3A Protein; D051176:beta Catenin / Q000378:metabolism
D026502:LDL-Receptor Related Proteins; C555482:LRP5 protein, human; D060492:Low Density Lipoprotein Receptor-Related Protein-5; C116415:Lrp4 protein, mouse; C555483:Lrp5 protein, mouse; D011973:Receptors, LDL; C555507:WNT3 protein, human; C555510:WNT3A protein, human; D051153:Wnt Proteins; D060508:Wnt3 Protein; C555508:Wnt3 protein, mouse; D060509:Wnt3A Protein; C555511:Wnt3a protein, mouse; D051176:beta Catenin