Targeting LRP8 inhibits breast cancer stem cells in triple-negative breast cancer

Abstract

Triple-negative breast cancer (TNBC) is the most difficult subtype of breast cancer to treat due to a paucity of effective targeted therapies. Many studies have reported that breast cancer stem cells (BCSCs) are enriched in TNBC and are responsible for chemoresistance and metastasis. In this study, we identify LRP8 as a novel positive regulator of BCSCs in TNBC. LRP8 is highly expressed in TNBC compared to other breast cancer subtypes and its genomic locus is amplified in 24% of TNBC tumors. Knockdown of LRP8 in TNBC cell lines inhibits Wnt/β-catenin signaling, decreases BCSCs, and suppresses tumorigenic potential in xenograft models. LRP8 knockdown also induces a more differentiated, luminal-epithelial phenotype and thus sensitizes the TNBC cells to chemotherapy. Together, our study highlights LRP8 as a novel therapeutic target for TNBC as inhibition of LRP8 can attenuate Wnt/β-catenin signaling to suppress BCSCs.

Integrin α9 depletion promotes β‐catenin degradation to suppress triple‐negative breast cancer tumor growth and metastasis

“…In our study, we found that ITGA9 downregulation promotes β‐catenin degradation, which may provide an alternative strategy for inhibiting β‐catenin pathway through targeting ITGA9. Indeed, ours and other recent studies provided additional support to this idea of targeting abnormally expressed or activated molecules in cancer cells that enhance β‐catenin signaling to reduce TNBC stemness, tumor growth and metastasis …”

“…Indeed, ours and other recent studies provided additional support to this idea of targeting abnormally expressed or activated molecules in cancer cells that enhance β-catenin signaling to reduce TNBC stemness, tumor growth and metastasis. 49,50 In summary, the findings from this study not only shed new light on TNBC biology and also reveal novel therapeutic opportunities with the potential to improve clinical outcomes of TNBC by targeting ITGA9.…”

Dissecting the heterogeneity of the alternative polyadenylation profiles in triple-negative breast cancers

“…Intriguingly, we observed a reversion of APA events occurred after CPSF1 or PABPN1 knockdown. The involved genes participate in drug resistance ( SCL9A1 38 , CCSAP 54 , NUP98 55 , PLD1 56 ), tumorigenesis ( DEPDC5 57 ), proliferation ( MED15 58 , STX3 59 ) and metastasis ( ARHGEF26 60 , ATP6V0A2 61 , MBD4 62 ) in breast cancer and are breast cancer biomarkers ( ITPR1 63 , NUP98 55 , GATA3 64 , 65 , DOCK4 66 , OSR1 67 ) and potential drug targets for TNBC ( SCL9A1 38 , LRP8 68 , 69 ). It suggests understanding APA regulation mediated by the core 3' processing factors, especially the target specificity and directionality, may provide new ideas for targeted therapy in TNBC.…”

Contribution of the Low-Density Lipoprotein Receptor Family to Breast Cancer Progression

“…The function of LRP8/ApoER2, strongly expressed in ER negative breast tumors was recently described in breast tumor initiating cells, which constitute a clinical challenge of the pathology ( 18 ). Interestingly, its depletion impairs TNBC cell proliferation and promotes apoptosis ( 19 ).…”

“…Interestingly, its depletion impairs TNBC cell proliferation and promotes apoptosis ( 19 ). LRP8 depletion also leads to Wnt/β-catenin signaling inhibition, decreases the pool of BC cells, limits their tumorigenic potential in murine xenografts, and finally restores TNBC cell sensitivity to chemotherapy ( 18 ). An overview of the complex and multiple LRPs-mediated signaling pathways is shown in Figure 1 .…”