LRP8 is overexpressed in estrogen‐negative breast cancers and a potential target for these tumors

• Published in: Cancer medicine (Malden, MA) MA), 2019-01, Vol.8 (1), p.325-336
• Main Authors: Maire, Virginie, Mahmood, Faisal, Rigaill, Guillem, Ye, Mengliang, Brisson, Amélie, Némati, Fariba, Gentien, David, Tucker, Gordon C., Roman‐Roman, Sergio, Dubois, Thierry
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Breast cancer; Cancer Biology; Cell Cycle; Cell death; Cell Line, Tumor; Cell Proliferation; DNA microarrays; ErbB-2 protein; Female; G1 phase; Gene expression; HER2; Humans; LDL-Receptor Related Proteins - genetics; Life Sciences; LRP8; Medical prognosis; Menopause; Mice, Nude; Original Research; Receptor density; targeted therapy; Triple Negative Breast Neoplasms - genetics; Triple Negative Breast Neoplasms - pathology; triple‐negative breast cancer; Tumor cell lines; Tumors; Vegetal Biology; Xenografts
• ISSN: 2045-7634; 2045-7634
• DOI: 10.1002/cam4.1923

Triple‐negative breast cancer (TNBC) is the breast cancer subtype with the worst prognosis. New treatments improving the survival of TNBC patients are, therefore, urgently required. We performed a transcriptome microarray analysis to identify new treatment targets for TNBC. We found that low‐density lipoprotein receptor‐related protein 8 (LRP8) was more strongly expressed in estrogen receptor‐negative breast tumors, including TNBCs and those overexpressing HER2, than in luminal breast tumors and normal breast tissues. LRP8 depletion decreased cell proliferation more efficiently in estrogen receptor‐negative breast cancer cell lines: TNBC and HER2 overexpressing cell lines. We next focused on TNBC cells for which targeted therapies are not available. LRP8 depletion induced an arrest of the cell cycle progression in G1 phase and programmed cell death. We also found that LRP8 is required for anchorage‐independent growth in vitro, and that its depletion in vivo slowed tumor growth in a xenograft model. Our findings suggest that new approaches targeting LRP8 may constitute promising treatments for hormone‐negative breast cancers, those overexpressing HER2 and TNBCs. LRP8 is a transmembrane receptor that has been extensively studied in the field of neuroscience, but rarely in the context of cancer. We show here that LRP8 is highly expressed in estrogen receptor‐negative breast tumors: ER‐/HER2+ and TNBC tumors. We show that LRP8 is essential for cell viability, due to its role in controlling cell cycle progression and apoptosis, and required for cell tumorigenesis both in vitro and in vivo. Our results identify LRP8 as a new potential candidate target for the treatment of estrogen receptor‐negative breast tumors.