title: Estrogen-dependent sushi domain containing 3 regulates cytoskeleton organization and migration in breast cancer cells.
abstract: Aromatase inhibitors (AIs) are the standard endocrine therapy for postmenopausal breast cancer; however, currently used biomarkers, such as, estrogen receptor-alpha/progesterone receptor (ERα/PR), predict only slightly more than half of the potential responders to AI treatment. To identify novel markers of AI responsiveness, a genome-wide microarray analysis was performed using primary breast tumor samples from 50 postmenopausal women who later developed metastatic breast cancer. Sushi domain containing 3 (SUSD3) is a significantly differentially expressed gene, with 3.38-fold higher mRNA levels in AI-responsive breast tumors vs non-responders (P<0.001). SUSD3 was highly expressed in ERα-positive breast tumors and treatment with estradiol increased SUSD3 expression in ERα-positive breast cancer cells. Treatment with an antiestrogen or ERα knockdown abolished basal and estradiol-dependent SUSD3 expression. Recruitment of ERα upstream of the transcription start site of SUSD3 was demonstrated by chromatin immunoprecipitation-PCR. Flow cytometric analysis of SUSD3-knockdown cells revealed blunted estradiol effects on progression into S and M phases. SUSD3 was localized to the plasma membrane of breast cancer cells. SUSD3 knockdown decreased the appearance of actin-rich protrusions, stress fibers and large basal focal adhesions, while increasing the presence of cortical actin concomitant with a decrease in Rho and focal adhesion kinase activity. SUSD3-deficient cells demonstrated diminished cell spreading, cell-cell adhesion and motility. In conclusion, SUSD3 is a novel promoter of estrogen-dependent cell proliferation and regulator of cell-cell and cell-substrate interactions and migration in breast cancer. It may serve as a novel predictor of response to endocrine therapy and potential therapeutic target.
authors.affiliation: Division of Reproductive Biology, Department of Obstetrics and Gynecology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: I
authors.initials: I
authors.lastname: Moy
authors.affiliation: Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: V
authors.initials: V
authors.lastname: Todorović
authors.affiliation: Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: A D
authors.initials: AD
authors.lastname: Dubash
authors.affiliation: Division of Reproductive Biology, Department of Obstetrics and Gynecology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: J S
authors.initials: JS
authors.lastname: Coon
authors.affiliation: Division of Reproductive Biology, Department of Obstetrics and Gynecology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: J B
authors.initials: JB
authors.lastname: Parker
authors.affiliation: Division of Reproductive Biology, Department of Obstetrics and Gynecology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: M
authors.initials: M
authors.lastname: Buranapramest
authors.affiliation: Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: C C
authors.initials: CC
authors.lastname: Huang
authors.affiliation: Division of Reproductive Biology, Department of Obstetrics and Gynecology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: H
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: K J
authors.initials: KJ
authors.lastname: Green
authors.affiliation: Division of Reproductive Biology, Department of Obstetrics and Gynecology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: S E
authors.initials: SE
authors.lastname: Bulun
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism*; D047072:Aromatase Inhibitors / Q000494:pharmacology; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics*; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology*; D065171:Estrogen Receptor Antagonists / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D004967:Estrogens / Q000494:pharmacology; D005260:Female; D022001:Focal Adhesions / Q000235:genetics; D000077267:Fulvestrant; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D061986:MCF-7 Cells; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D018613:Microscopy, Confocal; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D047072:Aromatase Inhibitors; D065171:Estrogen Receptor Antagonists; D047628:Estrogen Receptor alpha; D004967:Estrogens; D008565:Membrane Proteins; C000597072:SUSD3 protein, human; D000077267:Fulvestrant; D004958:Estradiol