title: HOXB13 mediates tamoxifen resistance and invasiveness in human breast cancer by suppressing ERα and inducing IL-6 expression.
abstract: Most breast cancers expressing the estrogen receptor α (ERα) are treated successfully with the receptor antagonist tamoxifen (TAM), but many of these tumors recur. Elevated expression of the homeodomain transcription factor HOXB13 correlates with TAM-resistance in ERα-positive (ER+) breast cancer, but little is known regarding the underlying mechanism. Our comprehensive evaluation of HOX gene expression using tiling microarrays, with validation, showed that distant metastases from TAM-resistant patients also displayed high HOXB13 expression, suggesting a role for HOXB13 in tumor dissemination and survival. Here we show that HOXB13 confers TAM resistance by directly downregulating ERα transcription and protein expression. HOXB13 elevation promoted cell proliferation in vitro and growth of tumor xenografts in vivo. Mechanistic investigations showed that HOXB13 transcriptionally upregulated interleukin (IL)-6, activating the mTOR pathway via STAT3 phosphorylation to promote cell proliferation and fibroblast recruitment. Accordingly, mTOR inhibition suppressed fibroblast recruitment and proliferation of HOXB13-expressing ER+ breast cancer cells and tumor xenografts, alone or in combination with TAM. Taken together, our results establish a function for HOXB13 in TAM resistance through direct suppression of ERα and they identify the IL-6 pathways as mediator of disease progression and recurrence.
authors.affiliation: Departments of Oncology, Surgery, and Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21231-1000, USA. nshahnb@gmail.com
authors.forename: Nilay
authors.initials: N
authors.lastname: Shah
authors.forename: Kideok
authors.initials: K
authors.lastname: Jin
authors.forename: Leigh-Ann
authors.initials: LA
authors.lastname: Cruz
authors.forename: Sunju
authors.initials: S
authors.lastname: Park
authors.forename: Helen
authors.initials: H
authors.lastname: Sadik
authors.forename: Soonweng
authors.initials: S
authors.lastname: Cho
authors.forename: Chirayu Pankaj
authors.initials: CP
authors.lastname: Goswami
authors.forename: Harikrishna
authors.initials: H
authors.lastname: Nakshatri
authors.forename: Rajnish
authors.initials: R
authors.lastname: Gupta
authors.forename: Howard Y
authors.initials: HY
authors.lastname: Chang
authors.forename: Zhe
authors.initials: Z
authors.lastname: Zhang
authors.forename: Ashley
authors.initials: A
authors.lastname: Cimino-Mathews
authors.forename: Leslie
authors.initials: L
authors.lastname: Cope
authors.forename: Christopher
authors.initials: C
authors.lastname: Umbricht
authors.forename: Saraswati
authors.initials: S
authors.lastname: Sukumar
mesh_terms: D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001940:Breast / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D015996:Survival Rate; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology*
chemical_list: D018931:Antineoplastic Agents, Hormonal; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; C484414:HOXB13 protein, human; D018398:Homeodomain Proteins; D015850:Interleukin-6; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; D013629:Tamoxifen; D008156:Luciferases; D058570:TOR Serine-Threonine Kinases