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

ABSTRACT: 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.

SUBMITTER: Maire V

PROVIDER: S-EPMC6346259 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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

Maire Virginie V Mahmood Faisal F Rigaill Guillem G Ye Mengliang M Brisson Amélie A Némati Fariba F Gentien David D Tucker Gordon C GC Roman-Roman Sergio S Dubois Thierry T

Cancer medicine 20181221 1

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 ...[more]

PMID: 30575334

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Project description:BackgroundSyndecan binding protein (SDCBP), an adapter protein containing PDZ domains, contributes to the tumorigenicity and metastasis of many malignant tumors, such as malignant melanoma. Our study aimed in revealing the expression profile of SDCBP in breast cancer (BCa) and its role in tumor cell proliferation, and then exploring its value in the targeted treatment of BCa.Methodology/principal findingsWe first evaluated the SDCBP expression by immunohistochemistry in normal breast and BCa tissues. Then we explored the expression profile of SDCBP in different BCa cell lines. By constructing SDCBP-silenced BCa cell clones, we further assessed the effects of SDCBP suppression on tumor cells in vitro by cell culture and in vivo by tumorigenicity. SDCBP expression was detected in 80.6% (n?=?160) of BCa tissues, in contrast to its expression in 13% (n?=?23) of normal breast tissues (P<0.001). Among the tumors, the level of its expression was positively correlated with histological grade and tumor staging while negatively correlated with the estrogen receptor (ER) expression. Higher expression of SDCBP was also noted in ER-negative BCa cell lines. It was also identified that SDCBP expression was down-regulated in a dose-dependent mode by 17-? estradiol in estrogen-responsive MCF-7. Furthermore, SDCBP silence inhibited ER-negative tumor cell growth in vivo and in vitro. Cell cycle studies showed that SDCBP silence increased G1 cell population and resulted in related cell-cycle-regulator changes: up-regulation of p21 and p27 while down-regulation of cyclin E.Conclusion/significanceOur results suggested that SDCBP played an important role in tumor growth of ER-negative BCas. In these tumors where the estrogen signaling pathway is not available, SDCBP probably contribute to tumor growth through an alternative signaling pathway by promoting tumor cells passing the G1/S checkpoint into the cell cycle. Suppression of SDCBP expression may have its potential to become a targeted therapy for ER-negative BCas.

Dataset Information

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

Publications

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

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