title: High-density and very-low-density lipoprotein have opposing roles in regulating tumor-initiating cells and sensitivity to radiation in inflammatory breast cancer.
abstract: OBJECTIVE
  We previously demonstrated that cholesterol-lowering agents regulate radiation sensitivity of inflammatory breast cancer (IBC) cell lines in vitro and are associated with less radiation resistance among IBC patients who undergo postmastectomy radiation. We hypothesized that decreasing IBC cellular cholesterol induced by treatment with lipoproteins would increase radiation sensitivity. Here, we examined the impact of specific transporters of cholesterol (ie lipoproteins) on the responses of IBC cells to self-renewal and to radiation in vitro and on clinical outcomes in IBC patients.
  
  
  METHODS
  Two patient-derived IBC cell lines, SUM 149 and KPL4, were incubated with low-density lipoproteins (LDL), very-low-density lipoproteins (VLDL), or high-density lipoproteins (HDL) for 24 hours prior to irradiation (0-6 Gy) and mammosphere formation assay. Cholesterol panels were examined in a cohort of patients with primary IBC diagnosed between 1995 and 2011 at MD Anderson Cancer Center. Lipoprotein levels were then correlated to patient outcome, using the log rank statistical model, and examined in multivariate analysis using Cox regression.
  
  
  RESULTS
  VLDL increased and HDL decreased mammosphere formation compared to untreated SUM 149 and KPL4 cells. Survival curves showed enhancement of survival in both of the IBC cell lines when pretreated with VLDL and, conversely, radiation sensitization in all cell lines when pretreated with HDL. In IBC patients, higher VLDL values (>30 mg/dL) predicted a lower 5-year overall survival rate than normal values (hazard ratio [HR] = 1.9 [95% confidence interval [CI]: 1.05-3.45], P=.035). Lower-than-normal patient HDL values (<60 mg/dL) predicted a lower 5-year overall survival rate than values higher than 60 mg/dL (HR = 3.21 [95% CI: 1.25-8.27], P=.015).
  
  
  CONCLUSIONS
  This study discovered a relationship among the plasma levels of lipoproteins, overall patient response, and radiation resistance in IBC patients and IBC patient-derived cell lines. A more expansive study is needed to verify these observations.
authors.affiliation: Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas; Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Adam R
authors.initials: AR
authors.lastname: Wolfe
authors.affiliation: Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Atkinson
authors.affiliation: Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jay P
authors.initials: JP
authors.lastname: Reddy
authors.affiliation: Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas; Department of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Bisrat G
authors.initials: BG
authors.lastname: Debeb
authors.affiliation: Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas; Department of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Richard
authors.initials: R
authors.lastname: Larson
authors.affiliation: Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas; Department of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Masuda
authors.affiliation: Department of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Takae
authors.initials: T
authors.lastname: Brewer
authors.affiliation: Department of Clinical Pharmacy Services, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Bradley J
authors.initials: BJ
authors.lastname: Atkinson
authors.affiliation: Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Abeena
authors.initials: A
authors.lastname: Brewster
authors.affiliation: Department of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Naoto T
authors.initials: NT
authors.lastname: Ueno
authors.affiliation: Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas; Department of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston, Texas. Electronic address: wwoodward@mdanderson.org.
authors.forename: Wendy A
authors.initials: WA
authors.lastname: Woodward
mesh_terms: D000924:Anticholesteremic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002784:Cholesterol / Q000032:analysis / Q000378:metabolism; D004260:DNA Repair; D050171:Dyslipidemias / Q000097:blood / Q000401:mortality; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D058922:Inflammatory Breast Neoplasms / Q000097:blood* / Q000401:mortality / Q000532:radiotherapy*; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008075:Lipoproteins, HDL / Q000097:blood* / Q000494:pharmacology; D008079:Lipoproteins, VLDL / Q000097:blood* / Q000494:pharmacology; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011836:Radiation Tolerance / Q000187:drug effects; D012044:Regression Analysis; D015996:Survival Rate; D014410:Tumor Stem Cell Assay
chemical_list: D000924:Anticholesteremic Agents; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D036341:Intercellular Signaling Peptides and Proteins; D008075:Lipoproteins, HDL; D008079:Lipoproteins, VLDL; C026277:very high density lipoproteins; D002784:Cholesterol; C512478:EGFR protein, human; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt
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