Layla Kutty

Background: Not only does breast cancer continue to affect the lives of women across the world at incredibly high rates, but it is closely associated with the prevalence of metastasis that specifically targets bone tissue^1,2. As a result, 60% of individuals with breast cancer also suffer from osteolytic lesions². This can lead to skeletal maladies such as weakness, mobility issues, and spinal cord compression⁴. This bone metastasis is a result of a combination of an increase in bone resorption by osteoclasts and reduced activity of bone formation by osteoblasts³. The Wnt-β Catenin pathway is thought to be heavily involved in the regulation of osteoblasts⁴. The Wnt-β catenin pathway uses the LRP 5/6 co-receptor to activate B-catenin⁴. This upregulates transcription factors that ultimately result in stem cells differentiating into osteoblasts and the amplification of osteoprotegerin, slowing osteoclast activity⁴. By regulating this pathway through SOST, DKK1, TWS119, and MTSS1 there is potential for reducing the rate of bone metastasis.

Objective: In this review, we discussed the various pathways that regulate the Wnt-β catenin pathway in order to find ways to reduce bone metastasis and preserve the bone microenvironment in breast cancer patients.

Search Methods: PubMed was used with the search terms “Wnt pathway”, “breast cancer”, “sclerostin”, “RANKL”, and “bone metastasis” between the years 2018 and 2024.

Results: Research shows that breast cancer cells have been found to secrete RANKL, which promotes osteoclast differentiation and provides an environment for the cells to metastasize⁸. In contrast to RANKL, the Wnt pathway is an important regulator of osteoblast differentiation⁹. Human bone marrow mesenchymal stem cells (hBMSCs) were treated with polydatin and it was found that polydatin increased osteogenic genes via the Wnt pathway⁹. The Wnt pathway resulted in higher levels of osteoblast-related mRNAs such as Runx2, DLX5, and Collagen type I⁹. Another molecule, SOST, was found to inhibit the Wnt-β catenin pathway by preventing the binding of the Wnt ligands¹. Setrusumab (Scl-Ab) treatment and siRNAs against sclerostin both helped increase osteoblast bone formation and reduce bone resorption¹. Next, DKK1 is an important factor in osteoclast precursor recruitment by inhibiting the canonical Wnt pathway, and RANKL is able to effectively enhance bone metastasis by regulating DKK1⁸. TWS119, a pyrrolopyrimidine, was effective in inhibiting DKK1 osteoclast precursor recruitment⁸. Lastly, MTSS1 and Src were obtained and cotransfected in one group of mice and MTSS1, Src, and siRNAs to silence MTSS1 were also transfected¹⁰. When MTSS1 was overexpressed, Src was not phosphorylated and Wnt-β catenin pathway components increased¹⁰. When Src was overexpressed, these components decreased¹⁰.

Conclusion: A clear relationship between the Wnt-β catenin pathway and SOST, DKK1, TWS119, and MTSS1 was established. This means there could be a potential link between the Wnt-β catenin pathway, these various molecules, and preventing susceptibility to bone metastasis. Mechanisms of treatment have effectively halted bone resorption through the inhibition of osteoclast activity but fail to reverse the damage already done to the bone¹.

Works Cited:

1. Hesse E, Schröder S, Brandt D, Pamperin J, Saito H, Taipaleenmäki H. Sclerostin inhibition alleviates breast cancer-induced bone metastases and muscle weakness. JCI Insight. 2019;5(9):e125543. Published 2019 Apr 9. doi:10.1172/jci.insight.125543
2. Cui J, Chen H, Zhang K, Li X. Targeting the Wnt signaling pathway for breast cancer bone metastasis therapy. J Mol Med (Berl). 2022;100(3):373-384. doi:10.1007/s00109-021-02159-y
3. Venetis K, Piciotti R, Sajjadi E, et al. Breast Cancer with Bone Metastasis: Molecular Insights and Clinical Management. Cells. 2021;10(6):1377. Published 2021 Jun 2. doi:10.3390/cells10061377
4. Ben-Ghedalia-Peled N, Vago R. Wnt Signaling in the Development of Bone Metastasis. Cells. 2022;11(23):3934. Published 2022 Dec 5. doi:10.3390/cells11233934
5. Michaels E, Worthington RO, Rusiecki J. Breast Cancer: Risk Assessment, Screening, and Primary Prevention. Med Clin North Am. 2023;107(2):271-284. doi:10.1016/j.mcna.2022.10.007
6. Zhang Y, Liang J, Liu P, Wang Q, Liu L, Zhao H. The RANK/RANKL/OPG system and tumor bone metastasis: Potential mechanisms and therapeutic strategies. Front Endocrinol (Lausanne). 2022;13:1063815. Published 2022 Dec 16. doi:10.3389/fendo.2022.1063815
7. Liu F, Ke J, Song Y. Application of Biomarkers for the Prediction and Diagnosis of Bone Metastasis in Breast Cancer. J Breast Cancer. 2020;23(6):588-598. doi:10.4048/jbc.2020.23.e65
8. Yue Z, Niu X, Yuan Z, et al. RSPO2 and RANKL signal through LGR4 to regulate osteoclastic premetastatic niche formation and bone metastasis. J Clin Invest. 2022;132(2):e144579. doi:10.1172/JCI144579
9. Chen XJ, Shen YS, He MC, et al. Polydatin promotes the osteogenic differentiation of human bone mesenchymal stem cells by activating the BMP2-Wnt/β-catenin signaling pathway. Biomed Pharmacother. 2019;112:108746. doi:10.1016/j.biopha.2019.108746
10. Chen M, Shan L, Gan Y, et al. Metastasis suppressor 1 controls osteoblast differentiation and bone homeostasis through regulating Src-Wnt/β-catenin signaling. Cell Mol Life Sci. 2022;79(2):107. Published 2022 Jan 30. doi:10.1007/s00018-022-041