Interleukin-6 is a potential therapeutic target in interleukin-6 dependent, estrogen receptor-α-positive breast cancer
Tineke Casneuf,1 Amy E Axel,2 Peter King,2 John D Alvarez,2 Jillian L Werbeck,3 Tinne Verhulst,1 Karin Verstraeten,1 Brett M Hall,2 A Kate Sasser2 1Janssen Research and Development, Beerse, Belgium; 2Janssen Research and Development, Spring House, PA, 3LabConnect LLC, Seattle, WA, USAIntroduction: I...
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Dove Medical Press
2016
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oai:doaj.org-article:6f201d7c161d4e79a4b2094aa928728e2021-12-02T05:24:55ZInterleukin-6 is a potential therapeutic target in interleukin-6 dependent, estrogen receptor-α-positive breast cancer1179-1314https://doaj.org/article/6f201d7c161d4e79a4b2094aa928728e2016-02-01T00:00:00Zhttps://www.dovepress.com/interleukin-6-is-a-potential-therapeutic-target-in-interleukin-6-depen-peer-reviewed-article-BCTThttps://doaj.org/toc/1179-1314Tineke Casneuf,1 Amy E Axel,2 Peter King,2 John D Alvarez,2 Jillian L Werbeck,3 Tinne Verhulst,1 Karin Verstraeten,1 Brett M Hall,2 A Kate Sasser2 1Janssen Research and Development, Beerse, Belgium; 2Janssen Research and Development, Spring House, PA, 3LabConnect LLC, Seattle, WA, USAIntroduction: Interleukin-6 (IL-6) is an important growth factor for estrogen receptor-α (ERα)-positive breast cancer, and elevated serum IL-6 is associated with poor prognosis.Methods: The role of the phosphorylated signal transducer and activator of transcription 3 pathway was investigated in ERα-positive breast cancer. A panel of cell lines was treated with exogenous IL-6. An IL-6 specific gene signature was generated by profiling ten ERα-positive breast cancer cell lines alone or following treatment with 10 ng/mL recombinant IL-6 or human marrow stromal cell-conditioned media, with or without siltuximab (a neutralizing anti-IL-6 antibody) and grown in three-dimensional tumor microenvironment-aligned cultures for 4 days, 5 days, or 6 days. The established IL-6 signature was validated against 36 human ERα-positive breast tumor samples with matched serum. A comparative MCF-7 xenograft murine model was utilized to determine the role of IL-6 in estrogen-supplemented ERa-positive breast cancer to assess the efficacy of anti-IL-6 therapy in vivo.Results: In eight of nine ERα-positive breast cancer cell lines, recombinant IL-6 increased phosphorylation of tyrosine 705 of STAT3. Differential gene expression analysis identified 17 genes that could be used to determine IL-6 pathway activation by combining their expression intensity into a pathway activation score. The gene signature included a variety of genes involved in immune cell function and migration, cell growth and apoptosis, and the tumor microenvironment. Validation of the IL-6 gene signature in 36 matched human serum and ERα-positive breast tumor samples showed that patients with a high IL-6 pathway activation score were also enriched for elevated serum IL-6 (≥10 pg/mL). When human IL-6 was provided in vivo, MCF-7 cells engrafted without the need for estrogen supplementation, and addition of estrogen to IL-6 did not further enhance engraftment. Subsequently, we prophylactically treated mice at MCF-7 engraftment with siltuximab, fulvestrant, or combination therapy. Siltuximab alone was able to blunt MCF-7 engraftment. Similarly, siltuximab alone induced regressions in 90% (9/10) of tumors, which were established in the presence which were established in the presence of hMSC expressing human IL-6 and estrogen.Conclusion: Given the established role for IL-6 in ERα-positive breast cancer, these data demonstrate the potential for anti-IL-6 therapeutics in breast cancer.Keywords: breast cancer, estrogen receptor, gene signature, paracrine IL-6, siltuximabCasneuf TAxel AEKing PAlvarez JDWerbeck JLVerhulst TVerstraeten KHall BMSasser AKDove Medical Pressarticlebreast cancerestrogen receptorgene signatureinterleukin-6siltuximabNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENBreast Cancer: Targets and Therapy, Vol 2016, Iss Issue 1, Pp 13-27 (2016) |
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breast cancer estrogen receptor gene signature interleukin-6 siltuximab Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 |
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breast cancer estrogen receptor gene signature interleukin-6 siltuximab Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Casneuf T Axel AE King P Alvarez JD Werbeck JL Verhulst T Verstraeten K Hall BM Sasser AK Interleukin-6 is a potential therapeutic target in interleukin-6 dependent, estrogen receptor-α-positive breast cancer |
| description |
Tineke Casneuf,1 Amy E Axel,2 Peter King,2 John D Alvarez,2 Jillian L Werbeck,3 Tinne Verhulst,1 Karin Verstraeten,1 Brett M Hall,2 A Kate Sasser2 1Janssen Research and Development, Beerse, Belgium; 2Janssen Research and Development, Spring House, PA, 3LabConnect LLC, Seattle, WA, USAIntroduction: Interleukin-6 (IL-6) is an important growth factor for estrogen receptor-α (ERα)-positive breast cancer, and elevated serum IL-6 is associated with poor prognosis.Methods: The role of the phosphorylated signal transducer and activator of transcription 3 pathway was investigated in ERα-positive breast cancer. A panel of cell lines was treated with exogenous IL-6. An IL-6 specific gene signature was generated by profiling ten ERα-positive breast cancer cell lines alone or following treatment with 10 ng/mL recombinant IL-6 or human marrow stromal cell-conditioned media, with or without siltuximab (a neutralizing anti-IL-6 antibody) and grown in three-dimensional tumor microenvironment-aligned cultures for 4 days, 5 days, or 6 days. The established IL-6 signature was validated against 36 human ERα-positive breast tumor samples with matched serum. A comparative MCF-7 xenograft murine model was utilized to determine the role of IL-6 in estrogen-supplemented ERa-positive breast cancer to assess the efficacy of anti-IL-6 therapy in vivo.Results: In eight of nine ERα-positive breast cancer cell lines, recombinant IL-6 increased phosphorylation of tyrosine 705 of STAT3. Differential gene expression analysis identified 17 genes that could be used to determine IL-6 pathway activation by combining their expression intensity into a pathway activation score. The gene signature included a variety of genes involved in immune cell function and migration, cell growth and apoptosis, and the tumor microenvironment. Validation of the IL-6 gene signature in 36 matched human serum and ERα-positive breast tumor samples showed that patients with a high IL-6 pathway activation score were also enriched for elevated serum IL-6 (≥10 pg/mL). When human IL-6 was provided in vivo, MCF-7 cells engrafted without the need for estrogen supplementation, and addition of estrogen to IL-6 did not further enhance engraftment. Subsequently, we prophylactically treated mice at MCF-7 engraftment with siltuximab, fulvestrant, or combination therapy. Siltuximab alone was able to blunt MCF-7 engraftment. Similarly, siltuximab alone induced regressions in 90% (9/10) of tumors, which were established in the presence which were established in the presence of hMSC expressing human IL-6 and estrogen.Conclusion: Given the established role for IL-6 in ERα-positive breast cancer, these data demonstrate the potential for anti-IL-6 therapeutics in breast cancer.Keywords: breast cancer, estrogen receptor, gene signature, paracrine IL-6, siltuximab |
| format |
article |
| author |
Casneuf T Axel AE King P Alvarez JD Werbeck JL Verhulst T Verstraeten K Hall BM Sasser AK |
| author_facet |
Casneuf T Axel AE King P Alvarez JD Werbeck JL Verhulst T Verstraeten K Hall BM Sasser AK |
| author_sort |
Casneuf T |
| title |
Interleukin-6 is a potential therapeutic target in interleukin-6 dependent, estrogen receptor-α-positive breast cancer |
| title_short |
Interleukin-6 is a potential therapeutic target in interleukin-6 dependent, estrogen receptor-α-positive breast cancer |
| title_full |
Interleukin-6 is a potential therapeutic target in interleukin-6 dependent, estrogen receptor-α-positive breast cancer |
| title_fullStr |
Interleukin-6 is a potential therapeutic target in interleukin-6 dependent, estrogen receptor-α-positive breast cancer |
| title_full_unstemmed |
Interleukin-6 is a potential therapeutic target in interleukin-6 dependent, estrogen receptor-α-positive breast cancer |
| title_sort |
interleukin-6 is a potential therapeutic target in interleukin-6 dependent, estrogen receptor-α-positive breast cancer |
| publisher |
Dove Medical Press |
| publishDate |
2016 |
| url |
https://doaj.org/article/6f201d7c161d4e79a4b2094aa928728e |
| work_keys_str_mv |
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