title: IL-33 facilitates endocrine resistance of breast cancer by inducing cancer stem cell properties.
abstract: Breast cancers with estrogen receptor (ER) expressions account for the majority of all clinical cases. Due to hormone therapy with tamoxifen, prognoses of patients with ER-positive breast cancer are significantly improved. However, endocrine resistance to tamoxifen is common and inevitable, leading to compromised efficacy of hormone therapy. Herein, we identify a crucial role of IL-33 in inducing endocrine resistance of breast cancer. IL-33 overexpression in breast cancer cells results in resistance to tamoxifen-induced tumor growth inhibition, while IL-33 knockdown corrects this problem. Mechanistically, IL-33 induces breast cancer stem cell properties evidenced by mammosphere formation and xenograft tumorigenesis, as well as expression of cancer stem cell genes including ALDH1A3, OCT4, NANOG and SOX2. In breast cancer patients, higher serum IL-33 levels portend advanced clinical stages, poorly differentiated cancer cells and tumor recurrence. IL-33 expression levels in patients' freshly isolated breast cancer cells predicts tamoxifen resistance and cancer stem cell features in individual patient. Collectively, IL-33 induces endocrine resistance of breast cancer by promoting cancer stem cell properties. These findings provide novel mechanisms connecting IL-33 with cancer pathogenesis and pinpoint IL-33 as a promising target for optimizing hormone therapy in clinical practice.
authors.affiliation: Center of Diagnosis and Treatment of Breast Disease, The Affiliated Hospital of Qingdao University, Qingdao 266071, China.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Hu
authors.affiliation: Department of Respiratory Medicine, The Affiliated Hospital of Qingdao University, Qingdao 266071, China.
authors.forename: Jiaxing
authors.initials: J
authors.lastname: Sun
authors.affiliation: Department of Respiratory Medicine, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.
authors.forename: Chunhong
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Clinical Laboratory, Qingdao Women & Children Hospital, Qingdao 266034, China.
authors.forename: Xiangmao
authors.initials: X
authors.lastname: Bu
authors.affiliation: Central Laboratory of Molecular Biology, The Affiliated Hospital of Qingdao University, Qingdao 266071, China.
authors.forename: Xiangping
authors.initials: X
authors.lastname: Liu
authors.affiliation: Center of Diagnosis and Treatment of Breast Disease, The Affiliated Hospital of Qingdao University, Qingdao 266071, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Mao
authors.affiliation: Center of Diagnosis and Treatment of Breast Disease, The Affiliated Hospital of Qingdao University, Qingdao 266071, China. Electronic address: wanghbshine@126.com.
authors.forename: Haibo
authors.initials: H
authors.lastname: Wang
mesh_terms: D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D000067596:Interleukin-33 / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D061986:MCF-7 Cells; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D000071317:Nanog Homeobox Protein / Q000235:genetics / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism; D011379:Prognosis; D034622:RNA Interference; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D018931:Antineoplastic Agents, Hormonal; D000067596:Interleukin-33; D000071317:Nanog Homeobox Protein; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; D011960:Receptors, Estrogen; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; D013629:Tamoxifen
keywords: Breast cancer; Cancer stem cell; Endocrine resistance; IL-33