title: A targeted RNAi screen of the breast cancer genome identifies KIF14 and TLN1 as genes that modulate docetaxel chemosensitivity in triple-negative breast cancer.
abstract: OBJECTIVE
  To identify biomarkers within the breast cancer genome that may predict chemosensitivity in breast cancer.
  
  
  METHODS
  We conducted an RNA interference (RNAi) screen within the breast cancer genome for genes whose loss-of-function enhanced docetaxel chemosensitivity in an estrogen receptor-negative, progesterone receptor-negative, and Her2-negative (ER-, PR-, and Her2-, respectively) breast cancer cell line, MDA-MB-231. Top candidates were tested for their ability to modulate chemosensitivity in 8 breast cancer cell lines and to show in vivo chemosensitivity in a mouse xenograft model.
  
  
  RESULTS
  From ranking chemosensitivity of 328 short hairpin RNA (shRNA) MDA-MB-231 cell lines (targeting 133 genes with known somatic mutations in breast cancer), we focused on the top two genes, kinesin family member 14 (KIF14) and talin 1 (TLN1). KIF14 and TLN1 loss-of-function significantly enhanced chemosensitivity in four triple-negative breast cancer (TNBC) cell lines (MDA-MB-231, HCC38, HCC1937, and Hs478T) but not in three hormone receptor-positive cell lines (MCF7, T47D, and HCC1428) or normal human mammary epithelial cells (HMEC). Decreased expression of KIF14, but not TLN1, also enhanced docetaxel sensitivity in a Her2-amplified breast cancer cell line, SUM190PT. Higher KIF14 and TLN1 expressions are found in TNBCs compared with the other clinical subtypes. Mammary fat pad xenografts of KIF14- and TLN1-deficient MDA-MB-231 cells revealed reduced tumor mass compared with control MDA-MB-231 cells after chemotherapy. KIF14 expression is also prognostic of relapse-free and overall survival in representative breast cancer expression arrays.
  
  
  CONCLUSIONS
  KIF14 and TLN1 are modulators of response to docetaxel and potential therapeutic targets in TNBC.
authors.affiliation: Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Stina Mui
authors.initials: SM
authors.lastname: Singel
authors.forename: Crystal
authors.initials: C
authors.lastname: Cornelius
authors.forename: Kimberly
authors.initials: K
authors.lastname: Batten
authors.forename: Gail
authors.initials: G
authors.lastname: Fasciani
authors.forename: Woodring E
authors.initials: WE
authors.lastname: Wright
authors.forename: Lawrence
authors.initials: L
authors.lastname: Lum
authors.forename: Jerry W
authors.initials: JW
authors.lastname: Shay
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D000077143:Docetaxel; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D055106:Genome-Wide Association Study / Q000379:methods; D006801:Humans; D053208:Kaplan-Meier Estimate; D016547:Kinesins / Q000235:genetics* / Q000378:metabolism; D061986:MCF-7 Cells; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D015513:Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D011379:Prognosis; D034622:RNA Interference; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D011980:Receptors, Progesterone / Q000235:genetics / Q000378:metabolism; D016608:Talin / Q000235:genetics* / Q000378:metabolism; D043823:Taxoids / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D000077143:Docetaxel; D016547:Kinesins; D015513:Oncogene Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D016608:Talin; D043823:Taxoids; C518832:TLN1 protein, human; C502598:KIF14 protein, human