Submitted Successfully!
Thank you for your contribution! You can also upload a video entry related to this topic through the link below: https://encyclopedia.pub/user/video_add?id=27536
Check Note
2000/2000
Ver. Summary Created by Modification Content Size Created at Operation
1 -- 1304 2022-09-23 12:18:46 |
2 format correct Meta information modification 1304 2022-09-26 03:33:16 |
EGFR in Inflammatory Breast Cancer
Edit
Upload a video

Epidermal growth factor receptor (EGFR), also called ErbB1 or HER1, belongs to ErbB family of receptors, which also includes HER2, HER3, and HER4. Inflammatory breast cancer (IBC) is the most lethal and aggressive form of breast cancer; it is highly likely to spread to other sites in the body. 

inflammatory breast cancer signaling pathways tumor microenvironment
Information
Subjects: Oncology
Contributors : , , , , , ,
View Times: 87
Revisions: 2 times (View History)
Update Date: 26 Sep 2022
Table of Contents

    1. Biological Functions of EGFR Pathway in IBC

    Upon binding to its ligands, EGFR forms an active homodimer or heterodimerizes with other ErbB family members such as HER2, activating downstream pathways involved in cell growth, proliferation, migration, and differentiation such as the mitogen-activated protein kinase (MAPK), AKT, c-Jun N-terminal kinase (JNK), and phosphoinositide phospholipase C/protein kinase C (PLC/PKC) signaling pathways. EGFR is overexpressed in IBC and other types of breast cancer [1][2]. EGFR expression independently predicts a high recurrence rate and shorter survival duration in patients with IBC. The 5-year overall survival rate of IBC patients with EGFR-positive disease is significantly lower than that of patients with EGFR-negative disease [1].
    EGFR signaling regulates tumor growth through its downstream AKT and ERK pathways. EGF and AREG ligands can activate EGFR signaling and promote the proliferation of IBC SUM149 cells in vitro [3]. In contrast, inactivation of the EGFR pathway using tyrosine kinase inhibitors gefitinib and erlotinib or EGFR knockdown suppressed the proliferation of IBC cells through the MAPK/ERK pathway as well as tumor growth in vivo [4][5]. Patients with IBC have a high tendency of distant metastasis. Erlotinib treatment reduces the invasion of IBC cells, reduces the expression of epithelial-to-mesenchymal transition (EMT) markers, and inhibits spontaneous lung metastasis in vivo [5].
    Patients with IBC have inflammatory clinical characteristics such as diffuse erythema and edema of the breast, and COX-2 is an important inflammatory molecule in IBC. Wang et al. [6] demonstrated that the expression of EGFR and COX-2 correlate with each other in IBC tumor biopsy samples and that EGFR regulates COX-2 expression in IBC cells.
    IBC patients have high expression of aldehyde dehydrogenase 1 (ALDH1), a CSC marker, which correlates with metastasis and worse patient outcome [7]. It has been reported that the EGFR pathway regulates CSC in IBC, as indicated by the reduced formation of primary and secondary mammospheres, and reduces CD44+/CD24− and ALDH+ populations—a hallmark of breast CSC—in IBC cells by the depletion of EGFR or inhibition of EGFR signaling [6]. The regulation of CSC by EGFR is mediated by COX-2 and nodal signaling in IBC.
    The EGFR pathway regulates the crosstalk between tumor cells and TME. Lacerda et al. [8] showed that the co-injection of MSCs with IBC SUM149 cells significantly increased skin invasion and metastasis in vivo, which are the clinical features of IBC. They also found a higher expression of phosphorylated EGFR (pEGFR) and more metastasis in tumors produced by the co-injection of SUM149 with mesenchymal stem cells compared with tumors grown from SUM149 cells only; the EGFR inhibitor erlotinib abrogated these effects [9]. In addition, the researchers showed that pEGFR expression in the stroma correlates with its expression in tumor cells in IBC patients but not in non-IBC patients [9]. TAMs are another main member of the TME and contribute to tumor progression and invasion by inducing immunosuppression, mediating tumor matrix remodeling, and supporting vascular potency [10][11][12]. Invasive tumor cells can migrate together with macrophages in primary mammary tumors in response to EGF and colony-stimulating factor 1 (CSF-1), which can be blocked by inhibiting either EGFR or CSF-1 signaling [13]. Macrophages also help tumor cells enter blood vessels; however, the inactivation of EGFR signaling blocks this process [14]. Treatment of human THP1 monocytes with erlotinib inhibited the polarization of M2 macrophages from monocytes (N.T. Ueno, unpublished data).

    2. Targeting EGFR Pathway in IBC

    Clinical trials of EGFR-targeted therapy for breast cancer patients have not shown clear clinical benefits.
    Erlotinib binds to the intracellular domains of EGFR and inhibits kinase activity and downstream signaling. In vitro studies indicated that erlotinib treatment inhibited IBC cell proliferation, anchorage-independent growth, cell motility, the COX-2 inflammatory pathway, and CSC marker-bearing cells in IBC [5][6]. In vivo, erlotinib reduced the growth of IBC primary tumors and metastasis to the lung [5].
    Panitumumab is a humanized anti-EGFR monoclonal antibody. It binds to EGFR and blocks the binding of EGF ligand, thus inactivating EGFR signaling. There have been two clinical studies of panitumumab in combination with neoadjuvant chemotherapy in patients with IBC (ClinicalTrials.gov Identifier: NCT01036087 and NCT02876107; Table 1). NCT01036087 (Phase II Study of Panitumumab, Nab-paclitaxel, and Carboplatin for Patients With Primary Inflammatory Breast Cancer (IBC) Without HER2 Overexpression) is a single-arm phase 2 study of neoadjuvant therapy with panitumumab, nab-paclitaxel, and carboplatin (PNC) followed by 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) in patients with newly diagnosed, HER2− primary IBC [15]. Patients received one dose of panitumumab followed by four cycles of PNC weekly and then four cycles of FEC every 3 weeks. The pCR rate was 28% in all evaluable patients, 42% in TN-IBC patients, and 14% in HR+/HER2− IBC patients. The treatment regimen had acceptable hematological and dermatological toxic effects, and there were no treatment-related deaths. A correlative study identified that pEGFR and COX-2 expression at baseline correlates with pCR. This trial indicates that panitumumab may enhance the response of IBC patients to neoadjuvant chemotherapy.
    Table 1. Clinical trials in inflammatory breast cancer.
    The definitive role of EGFR-targeted therapy will be further determined by an ongoing randomized phase 2 study of carboplatin and paclitaxel with and without panitumumab in TN-IBC patients (ClinicalTrials.gov Identifier: NCT02876107; A Randomized Phase II Study of Neoadjuvant Carboplatin/Paclitaxel (CT) Versus Panitumumab/Carboplatin/Paclitaxel (PaCT) Followed by Anthracycline-Containing Regimen for Newly Diagnosed Primary Triple-Negative Inflammatory Breast Cancer.) [16]. This trial plans to recruit 72 patients and randomize them into two arms. In Arm A, patients receive panitumumab as a single agent in the window period followed by weekly panitumumab and paclitaxel and triweekly carboplatin for a total of four cycles. Patients in Arm B receive the same regimen as those in Arm A but without panitumumab. In both arms, this treatment will be followed by treatment with doxorubicin and cyclophosphamide for 4 cycles and then surgery. The pCR, disease-free survival, and overall survival (OS) rates, as well as the safety and tolerability of treatment regimens, will be determined.
    Neratinib is a pan-EGFR receptor tyrosine kinase inhibitor that interacts with the catalytic domain of EGFR, HER2, and HER4. A phase II study of neratinib, pertuzumab, and trastuzumab with paclitaxel followed by doxorubicin and cyclophosphamide in HER2+ primary IBC, and neratinib with paclitaxel followed by doxorubicin and cyclophosphamide in HR+/HER2− primary IBC is ongoing (ClinicalTrials.gov Identifier: NCT03101748; Table 1) [17]. This study will determine the efficacy of neratinib with paclitaxel and with or without pertuzumab and trastuzumab in IBC and metastatic breast cancer.

    References

    1. Cabioglu, N.; Gong, Y.; Islam, R.; Broglio, K.; Sneige, N.; Sahin, A.; Gonzalez-Angulo, A.; Morandi, P.; Bucana, C.; Hortobagyi, G.; et al. Expression of growth factor and chemokine receptors: New insights in the biology of inflammatory breast cancer. Ann. Oncol. 2007, 18, 1021–1029.
    2. Corkery, B.; Crown, J.; Clynes, M.; O’Donovan, N. Epidermal growth factor receptor as a potential therapeutic target in triple-negative breast cancer. Ann. Oncol. 2009, 20, 862–867.
    3. Willmarth, N.E.; Ethier, S.P. Autocrine and Juxtacrine Effects of Amphiregulin on the Proliferative, Invasive, and Migratory Properties of Normal and Neoplastic Human Mammary Epithelial Cells. J. Boil. Chem. 2006, 281, 37728–37737.
    4. Stratford, A.L.; Habibi, G.; Astanehe, A.; Jiang, H.; Hu, K.; Park, E.; Shadeo, A.; Buys, T.P.H.; Lam, W.L.; Pugh, T.J.; et al. Epidermal growth factor receptor (EGFR) is transcriptionally induced by the Y-box binding protein-1 (YB-1) and can be inhibited with Iressa in basal-like breast cancer, providing a potential target for therapy. Breast Cancer Res. 2007, 9, R61.
    5. Zhang, N.; LaFortune, T.A.; Krishnamurthy, S.; Esteva, F.J.; Cristofanilli, M.; Liu, P.; Lucci, A.; Singh, B.; Hung, M.-C.; Hortobagyi, G.N.; et al. Epidermal growth factor receptor tyrosine kinase inhibitor reverses mesenchymal to epithelial phenotype and inhibits metastasis in inflammatory breast cancer. Clin. Cancer Res. 2009, 15, 6639–6648.
    6. Wang, X.; Reyes, M.E.; Zhang, D.; Funakoshi, Y.; Trape, A.P.; Gong, Y.; Kogawa, T.; Eckhardt, B.L.; Masuda, H.; Pirman, D.A.; et al. EGFR signaling promotes inflammation and cancer stem-like activity in inflammatory breast cancer. Oncotarget 2017, 8, 67904–67917.
    7. Charafe-Jauffret, E.; Ginestier, C.; Iovino, F.; Tarpin, C.; Diebel, M.; Esterni, B.; Houvenaeghel, G.; Extra, J.-M.; Bertucci, F.; Jacquemier, J.; et al. Aldehyde dehydrogenase 1-positive cancer stem cells mediate metastasis and poor clinical outcome in inflammatory breast cancer. Clin. Cancer Res. 2009, 16, 45–55.
    8. Allen, S.G.; Chen, Y.-C.; Madden, J.M.; Fournier, C.L.; Altemus, M.A.; Hiziroglu, A.B.; Cheng, Y.-H.; Wu, Z.F.; Bao, L.; Yates, J.; et al. Macrophages Enhance Migration in Inflammatory Breast Cancer Cells via RhoC GTPase Signaling. Sci. Rep. 2016, 6, 39190.
    9. Lacerda, L.; Debeb, B.G.; Smith, D.; A Larson, R.; Solley, T.; Xu, W.; Krishnamurthy, S.; Gong, Y.; Levy, L.B.; A Buchholz, T.; et al. Mesenchymal stem cells mediate the clinical phenotype of inflammatory breast cancer in a preclinical model. Breast Cancer Res. 2015, 17, 42.
    10. Quail, D.F.; Joyce, J.A. Microenvironmental regulation of tumor progression and metastasis. Nat. Med. 2013, 19, 1423–1437.
    11. Schmidt, T.; Ben-Batalla, I.; Schultze, A.; Loges, S. Macrophage–tumor crosstalk: Role of TAMR tyrosine kinase receptors and of their ligands. Cell. Mol. Life Sci. 2011, 69, 1391–1414.
    12. Su, S.; Liu, Q.; Chen, J.; Chen, J.; Chen, F.; He, C.; Huang, D.; Wu, W.; Lin, L.; Huang, W.; et al. A Positive Feedback Loop between Mesenchymal-like Cancer Cells and Macrophages Is Essential to Breast Cancer Metastasis. Cancer Cell 2014, 25, 605–620.
    13. Wang, W.; Goswami, S.; Sahai, E.; Wyckoff, J.B.; Segall, J.E.; Condeelis, J.S. Tumor cells caught in the act of invading: Their strategy for enhanced cell motility. Trends Cell Boil. 2005, 15, 138–145.
    14. Wyckoff, J.B. A Paracrine Loop between Tumor Cells and Macrophages Is Required for Tumor Cell Migration in Mammary Tumors. Cancer Res. 2004, 64, 7022–7029.
    15. Matsuda, N.; Wang, X.; Lim, B.; Krishnamurthy, S.; Alvarez, R.H.; Willey, J.S.; Parker, C.A.; Song, J.; Shen, Y.; Hu, J.; et al. Safety and Efficacy of Panitumumab Plus Neoadjuvant Chemotherapy in Patients With Primary HER2-Negative Inflammatory Breast Cancer. JAMA Oncol. 2018, 4, 1207–1213.
    16. Carboplatin and Paclitaxel With or Without Panitumumab in Treating Patients With Invasive Triple Negative Breast Cancer. Available online: https://ClinicalTrials.gov/show/NCT02876107 (accessed on 23 August 2016).
    17. Neratinib and Paclitaxel With or Without Pertuzumab and Trastuzumab Before Combination Chemotherapy in Treating Patients With Metastatic or Locally Advanced Breast Cancer. Available online: https://ClinicalTrials.gov/show/NCT03101748 (accessed on 5 April 2017).
    More
    Information
    Subjects: Oncology
    Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register : , , , , , ,
    View Times: 87
    Revisions: 2 times (View History)
    Update Date: 26 Sep 2022
    Table of Contents
      1000/1000

      Confirm

      Are you sure you want to delete?

      Video Upload Options

      Do you have a full video?
      Cite
      If you have any further questions, please contact Encyclopedia Editorial Office.
      Wang, X.; Semba, T.; Phi, L.T.H.; Chainitikun, S.; Iwase, T.; Lim, B.; Ueno, N.T. EGFR in Inflammatory Breast Cancer. Encyclopedia. Available online: https://encyclopedia.pub/entry/27536 (accessed on 07 February 2023).
      Wang X, Semba T, Phi LTH, Chainitikun S, Iwase T, Lim B, et al. EGFR in Inflammatory Breast Cancer. Encyclopedia. Available at: https://encyclopedia.pub/entry/27536. Accessed February 07, 2023.
      Wang, Xiaoping, Takashi Semba, Lan Thi Hanh Phi, Sudpreeda Chainitikun, Toshiaki Iwase, Bora Lim, Naoto T. Ueno. "EGFR in Inflammatory Breast Cancer," Encyclopedia, https://encyclopedia.pub/entry/27536 (accessed February 07, 2023).
      Wang, X., Semba, T., Phi, L.T.H., Chainitikun, S., Iwase, T., Lim, B., & Ueno, N.T. (2022, September 23). EGFR in Inflammatory Breast Cancer. In Encyclopedia. https://encyclopedia.pub/entry/27536
      Wang, Xiaoping, et al. ''EGFR in Inflammatory Breast Cancer.'' Encyclopedia. Web. 23 September, 2022.
      Top
      Feedback