Novel Biomarkers in Breast Cancer

Breast cancer is the most prevalent cancer among women globally. Enhancing our knowledge of how breast cancer develops, progresses, and metastasizes could aid in decreasing the risk and impact of the disease. Circulating proteins in serum or plasma can serve as biomarkers of cancer progression and prognosis while also serving as potential therapeutic targets. Enhancing our understanding on how cancers originate, grow and spread could aid in lowering the risk and impact of the disease. Recent research on cancer markers has highlighted novel protein biomarkers and promising therapeutic targets in breast cancer:

PERIOSTIN, NEUROPILIN-1, SEMAPHORIN 4D, and LEUCINE-RICH ALPHA-2-GLYCOPROTEIN. These proteins can be easily detected in human serum and plasma using ELISA assays.

Novel Biomarkers in Breast Cancer

PERIOSTIN (alternative names: POSTN, OSF-2, OSF2, PDLPN, PN)

Periostin is a matricellular protein that plays a significant role in various physiological and pathological processes, including tissue remodeling, inflammation, and wound healing. In the context of breast cancer, periostin has garnered attention due to its involvement in tumorigenesis, progression, and the tumor microenvironment.

Role of Periostin in Breast Cancer

Tumor Microenvironment: Periostin is often overexpressed in the extracellular matrix (ECM) of breast tumors (1). It interacts with various cells in the tumor microenvironment, including cancer-associated fibroblasts, immune cells, and endothelial cells, promoting tumor growth and metastasis. A recent study has demonstrated that Periostin drives extracellular matrix degradation, stemness, and chemoresistance in triple-negative breast cancer cells by activating specific signaling pathways (2).

Cell Signaling: Periostin can activate multiple signaling pathways that contribute to cancer progression. It is known to bind to integrins on the surface of cancer cells, which can lead to enhanced cell survival, proliferation, and migration. This signaling also supports processes such as epithelial-to-mesenchymal transition (EMT), a critical step in cancer metastasis.

Metastasis: Elevated levels of periostin have been associated with increased metastasis in breast cancer. Studies have indicated that higher periostin expression correlates with the aggressive behavior of breast cancer cells, particularly in triple-negative breast cancer (TNBC), which is known for its poor prognosis (3).

Periostin as a Potential Biomarker: Due to its association with poor outcomes and aggressive disease, periostin has been investigated as a potential biomarker for breast cancer. Its expression levels in tumor tissues or serum may provide insights into disease progression and treatment responses. Epithelial periostin expression is correlated with poor survival in patients with invasive breast carcinoma (3). High serum levels of Periostin have been demonstrated to be associated with poor survival in breast cancer (4).

Therapeutic Target: Given its role in promoting cancer progression, periostin presents a potential therapeutic target. Inhibition of periostin signaling may offer a novel strategy for treating aggressive breast cancer subtypes by disrupting the supportive tumor microenvironment (5).

Conclusion: Periostin plays a multifaceted role in breast cancer, affecting tumor growth, metastasis, and the tumor microenvironment. Its involvement in key molecular pathways and its potential utility as a biomarker make it a significant focus of ongoing research. Targeting periostin could open new avenues for therapy, particularly in aggressive forms of breast cancer, ultimately aiming to improve patient outcomes. Further studies are needed to fully elucidate its mechanisms and to evaluate its efficacy as a therapeutic target in clinical settings.

Periostin can reliably be measured in human blood samples with a conventional ELISA assay developed and manufactured by BIOMEDICA.

PERIOSTIN ELISA (cat. no. BI-20433)

• EASY – ready to use calibrators & controls included
• RELIABLE – validated according to international quality guidelines
• LOW sample volume- 10 µl / sample
• TRUSTED – widely cited

 

An in-depth characterization of the Biomedica Periostin ELISA has been published here: Characterization of a sandwich ELISA for the quantification of all human periostin isoforms. Gadermaier E et al., J Clin Lab Anal. 2018; 32(2):e22252.

 

Novel Biomarkers in Breast Cancer

NEUROPILIN-1 (alternative names: NRP1, BDCA4, CD304, NP1, NRP, VEGF165R)

Neuropilin-1 (NRP1) is a transmembrane protein that has emerged as an important player in breast cancer biology. It is involved in various cellular processes, including cell signaling, survival, and migration, and has been implicated in cancer progression and metastasis (6).

Role of Neuropilin-1 in Breast Cancer

Tumor Growth and Survival: Neuropilin-1 (NRP1) is expressed in both cancer cells and the surrounding stromal cells within the tumor microenvironment. It has been linked to enhanced cell survival and proliferation, contributing to tumor growth. Elevated NRP1 expression has been associated with aggressive breast cancer subtypes, such as triple-negative breast cancer (TNBC) (6). A recent study has demonstrated that high NRP1 expression is associated with shorter relapse- and metastasis-free survival specifically in ER-negative BrCa cohorts (7).

Angiogenesis: NRP1 plays a critical role in angiogenesis, the formation of new blood vessels from existing ones, which is crucial for tumor growth and metastasis. By interacting with vascular endothelial growth factor (VEGF) and its receptors, NRP1 promotes endothelial cell proliferation and migration, facilitating the tumor’s ability to establish a blood supply (8).

Metastasis: Neuropilin-1 expression has been shown to be associated with lymph node metastasis in breast cancer tissues (9). Increased levels of NRP1 in breast cancer have been correlated with a higher propensity for metastasis. Studies have shown that NRP1 facilitates the migration of cancer cells to distant sites, contributing to the spread of the disease and poorer patient outcomes.

Potential Biomarker: In breast cancer patients, soluble Neuropilin-1 has shown to be an independent marker of poor prognosis in early breast cancer (10). In addition NRP-1 has also been shown to be a potential biomarker of prognosis and invasive-related parameters in other cancers such as liver and colorectal cancer (11).

Therapeutic Target: Given its involvement in tumor growth, angiogenesis, and metastasis, NRP1 is being explored as a therapeutic target. Strategies to inhibit NRP1 function or block its signaling pathways could offer new avenues for breast cancer treatment, particularly for patients with aggressive or metastatic disease (12).

Conclusion: Neuropilin-1 is a significant factor in the biology of breast cancer, influencing tumor growth, metastasis, and interactions within the tumor microenvironment. Its role in promoting angiogenesis and facilitating aggressive cellular behaviors makes it an important target for ongoing research. Targeting NRP1 could provide new therapeutic approaches for breast cancer, potentially improving outcomes for patients, especially those with more aggressive forms of the disease. Further studies are needed to clarify its mechanisms and evaluate targeted therapies in clinical settings.

Neuropilin-1 (NRP1) can reliably be measured in human blood samples with a conventional ELISA assay developed and manufactured by BIOMEDICA.

Total soluble NEUROPILIN-1 ELISA (cat. no. BI-20409)

• EASY – ready to use calibrators & controls included
• RELIABLE – validated according to international quality guidelines
• LOW sample volume- 10 µl / sample
• TRUSTED – for citations click here

 

The Biomedica human NRP-1 ELISA is described in this following publication: Characterization of a sandwich ELISA for quantification of total human soluble neuropilin-1. Gadermaier E, Tesarz M, Wallwitz J, Berg G, Himmler G. J Clin Lab Anal. 2019; 33(7):e22944. doi: 10.1002/jcla.22944. PMID: 31219204.

 

Novel Biomarkers in Breast Cancer

SEMAPHORIN 4D (alternative names: Sema4D, C9orf164, SEMAJ, CD100, BB18, GR3, CD100, COLL4)

Semaphorin 4D (Sema4D) is a member of the semaphorin family of proteins, which are known for their roles in cell signaling, axon guidance, and immune regulation (13). In the context of breast cancer, Sema4D has garnered attention for its involvement in tumor growth, metastasis, and the tumor microenvironment.

About Semaphorin 4D in Breast Cancer

Tumor Growth and Progression: Sema4D can influence the behavior of cancer cells, promoting survival and proliferation. It may also aid in the establishment of a supportive tumor microenvironment. In a study researchers have shown that Sema4D was expressed at higher levels in breast cancer cell lines compared with the normal human breast epithelial cell lines (14).

Angiogenesis: Sema4D is involved in the formation of new blood vessels (angiogenesis), which is vital for tumor growth. It can modulate the activity of endothelial cells, thereby supporting the vascularization of tumors (14).

Immune Evasion: Sema4D can affect the immune response to tumors. It may contribute to the suppression of T-cell responses, allowing cancer cells to evade immune detection and destruction.

Metastasis: The expression of Sema4D has been linked to increased metastatic potential in breast cancer. It may facilitate the migration and invasion of cancer cells to distant sites in the body. In a recent study researchers have found that Semaphorin 4D promotes skeletal metastasis in breast cancer (15).

A decreased expression of semaphorin 4D and plexin-B in breast cancer has been shown to be associated with recurrence and poor prognosis in a breast cancer cohort (16).

Biomarker Potential: Research suggests that Sema4D levels could serve as a potential biomarker for breast cancer progression and prognosis, although further studies would be needed to establish its clinical utility.

The potential link between Sema4D and estrogen receptor signaling was proposed in a study measuring circulating Sema4D plasma levels at primary diagnosis and in a follow-up sample 12 months after surgery in a cohort of 46 pre- and postmenopausal women with primary estrogen receptor positive breast cancer receiving adjuvant tamoxifen. The finding potentially represents an additional mechanism of the bone-protective properties of tamoxifen (17).

Therapeutic Targeting:  Due to its involvement in various aspects of cancer biology, Sema4D is being explored as a potential therapeutic target. Inhibiting its function might help in reducing tumor growth and improving the effectiveness of existing treatments. A study demonstrated that a Sema4D antibody in combination with either CTLA-4 or PD-1 blockade enhanced rejection of tumors or tumor growth delay, resulting in prolonged survival with either treatment (18).

Conclusion: Sema4D plays a multifaceted role in breast cancer pathology, influencing tumor growth, metastasis, and immune interactions. Ongoing research is essential to fully understand its mechanisms and to explore its potential as a target for therapeutic intervention.

Soluble SEMAPHORIN 4D ELISA (cat. no. BI-20405)

• EASY – ready to use calibrators & controls included
• RELIABLE – first validated according to international quality guidelines
• LOW sample volume- 10 µl / sample – no predilution!
• Reference values for healthy individuals provided

 

An in-depth characterization of the Biomedica Semaphorin 4D ELISA has been published here: A high-sensitivity enzyme immunoassay for the quantification of soluble human semaphorin 4D in plasma. Laber, A., Gadermaier, E., Wallwitz, J., Berg, G., Himmler, G., 2019. Anal. Biochem. 574, 15–22.  PMID: 30879960

 

Novel Biomarkers in Breast Cancer

LEUCINE-RICH ALPHA-2-GLYCOPROTEIN (alternative names: LRG, LRG1, HMFT1766) 

Leucine-rich alpha-2-glycoprotein (LRG) is a protein that has been studied in various diseases, including cancer. It is known for its involvement in inflammation and immune responses. In the context of breast cancer, LRG has attracted interest for its potential role as a biomarker and its involvement in the tumor microenvironment. For more information on LRG-1 as a prognostic marker for breast cancer survival please click here

LRG ELISA Assay Highlights (cat. no. BI-LRG)

• CONVENIENT – ready to use reagents and controls included
• RELIABLE – rigorously validated following international quality guidelines
• EASY – results available in 3 hours

 

Related products

DKK-1 (Dickkopf-1) ELISA kit (cat. no. BI-20413) 

• Direct measurement – no sample pre-dilution
• Day test – all reagents included
• Widely cited +180 references!

 

Literature 

1.  Expression of periostin in breast cancer cells. Ratajczak-Wielgomas K, Grzegrzolka J, Piotrowska A, Matkowski R, Wojnar A, Rys J, Ugorski M, Dziegiel P. Int J Oncol. 2017; 51(4):1300-1310. doi: 10.3892/ijo.2017.4109.
2. Periostin drives extracellular matrix degradation, stemness, and chemoresistance by activating the MAPK/ERK signaling pathway in triple-negative breast cancer cells. Wu J, Li J, Xu H, Qiu N, Huang X, Li H. Lipids Health Dis. 2023; 16;22(1):153. doi: 10.1186/s12944-023-01912-1.
3. Epithelial periostin expression is correlated with poor survival in patients with invasive breast carcinoma. Kim GE, Lee JS, Park MH, Yoon JH. PLoS One. 2017; 21;12(11):e0187635. doi: 10.1371/journal.pone.0187635. PMID: 29161296..
4. High serum levels of periostin are associated with a poor survival in breast cancer. Rachner TD et al., Breast Cancer Res Treat. 2020; 180(2):515-524.
5. Development of an engineered peptide antagonist against periostin to overcome doxorubicin resistance in breast cancer. Oo KK, Kamolhan T, Soni A, Thongchot S, Mitrpant C, O-Charoenrat P, Thuwajit C, Thuwajit P. BMC Cancer. 2021; 14;21(1):65. doi: 10.1186/s12885-020-07761-w.
6. Neuropilin1, a novel independent prognostic factor and therapeutic target in triple-negative breast cancer. Wang H, Zhang YN, Xu DQ, Huang JG, Lv D, Shi XY, Liu JY, Ren HW, Han ZX. Neoplasma. 2020; 67(6):1335-1342. doi: 10.4149/neo_2020_191127N1223. PMID: 32657612.
7. Neuropilin-1 is over-expressed in claudin-low breast cancer and promotes tumor progression through acquisition of stem cell characteristics and RAS/MAPK pathway activation. Tang YH, Rockstroh A, Sokolowski KA, Lynam LR, Lehman M, Thompson EW, Gregory PA, Nelson CC, Volpert M, Hollier BG. Breast Cancer Res. 2022; 25;24(1):8. doi: 10.1186/s13058-022-01501-7. PMID: 35078508.
8. Endothelial VEGFR Coreceptors Neuropilin-1 and Neuropilin-2 Are Essential for Tumor Angiogenesis. Benwell CJ, Johnson RT, Taylor JAGE, Price CA, Robinson SD. Cancer Res Commun. 2022 Dec 14;2(12):1626-1640. doi: 10.1158/2767-9764.CRC-22-0250. PMID: 36970722; PMCID: PMC10036134.
9. Neuropilin-1 expression is associated with lymph node metastasis in breast cancer tissues. Seifi-Alan M, Shams R, Bandehpour M, Mirfakhraie R, Ghafouri-Fard S. Cancer Manag Res. 2018 Jul 11;10:1969-1974. doi: 10.2147/CMAR.S169533. PMID: 30022855; PMCID: PMC6045910.
10. Soluble Neuropilin-1 is an independent marker of poor prognosis in early breast cancer. Rachner TD, Kasimir-Bauer S, Goebel A, Erdmann K, Hoffmann O, Rauner M, Hofbauer LC, Kimmig R, Bittner AK. J Cancer Res Clin Oncol. 2021; 147(8):2233-2238. doi: 10.1007/s00432-021-03635-1. PMID: 33884469.
11. Neuropilin-1 as a Potential Biomarker of Prognosis and Invasive-Related Parameters in Liver and Colorectal Cancer: A Systematic Review and Meta-Analysis of Human Studies. Fernández-Palanca P, Payo-Serafín T, Fondevila F, Méndez-Blanco C, San-Miguel B, Romero MR, Tuñón MJ, Marin JJG, González-Gallego J, Mauriz JL. Cancers (Basel). 2022 Jul 15;14(14):3455. doi: 10.3390/cancers14143455. PMID: 35884516.
12. SPECT and near-infrared fluorescence imaging of breast cancer with a neuropilin-1-targeting peptide. Feng GK, Liu RB, Zhang MQ, Ye XX, Zhong Q, Xia YF, Li MZ, Wang J, Song EW, Zhang X, Wu ZZ, Zeng MS.J Control Release. 2014; 28;192:236-42. doi: 10.1016/j.jconrel.2014.07.039. PMID: 25058570.
13. Semaphorin 4D as a guidance molecule in the immune system. Kuklina E. Int Rev Immunol. 2021;40(4):268-273. doi: 10.1080/08830185.2021.1905807. PMID: 33787446.
14. The role of semaphorin 4D in tumor development and angiogenesis in human breast cancer. Jiang H, Chen C, Sun Q, Wu J, Qiu L, Gao C, Liu W, Yang J, Jun N, Dong J. Onco Targets Ther. 2016 Sep 26;9:5737-5750. doi: 10.2147/OTT.S114708. PMID: 27729799; PMCID: PMC5045906.
15. Semaphorin 4D Promotes Skeletal Metastasis in Breast Cancer. Yang YH, Buhamrah A, Schneider A, Lin YL, Zhou H, Bugshan A, Basile JR.PLoS One. 2016; 11(2):e0150151. doi: 10.1371/journal.pone.0150151. PMID: 26910109.
16. Reduced expression of semaphorin 4D and plexin-B in breast cancer is associated with poorer prognosis and the potential linkage with oestrogen receptor. Malik MF, Ye L, Jiang WG. Oncol Rep. 2015 Aug;34(2):1049-57. doi: 10.3892/or.2015.4015. Epub 2015 May 28. PMID: 26035216.
17. Plasma levels of Semaphorin 4D are decreased by adjuvant tamoxifen but not aromatase inhibitor therapy in breast cancer patients. Göbel, A., Kuhlmann, J.D., Link, T., Wimberger, P., Link-Rachner, C., Thiele, S., Dell’Endice, S., Furesi, G., Breining, D., Rauner, M., Hofbauer, L.C., Rachner, T.D., 2019. Journal of Bone Oncology, 16: 100237. PMID: 31011525
18. Semaphorin4D Inhibition Improves Response to Immune-Checkpoint Blockade via Attenuation of MDSC Recruitment and Function. Clavijo PE, Friedman J, Robbins Y, Moore EC, Smith E, Zauderer M, Evans EE, Allen CT. Cancer Immunol Res. 2019; 7(2):282-291. doi: 10.1158/2326-6066.CIR-18-0156. PMID: 30514791.