High-density and very-low-density lipoprotein have opposing roles in regulating tumor-initiating cells and sensitivity to radiation in inflammatory breast cancer

Int J Radiat Oncol Biol Phys. 2015 Apr 1;91(5):1072-80. doi: 10.1016/j.ijrobp.2014.12.039.


Purpose: 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 and materials: 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.

MeSH terms

  • Anticholesteremic Agents / pharmacology
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cholesterol / analysis
  • Cholesterol / metabolism
  • DNA Repair
  • Dyslipidemias / blood
  • Dyslipidemias / mortality
  • ErbB Receptors / metabolism
  • Female
  • Forkhead Box Protein O3
  • Forkhead Transcription Factors / metabolism
  • Humans
  • Inflammatory Breast Neoplasms / blood*
  • Inflammatory Breast Neoplasms / mortality
  • Inflammatory Breast Neoplasms / radiotherapy*
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Lipoproteins, HDL / blood*
  • Lipoproteins, HDL / pharmacology
  • Lipoproteins, VLDL / blood*
  • Lipoproteins, VLDL / pharmacology
  • Middle Aged
  • Neoplastic Stem Cells / drug effects
  • Neoplastic Stem Cells / physiology*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Radiation Tolerance* / drug effects
  • Regression Analysis
  • Survival Rate
  • Tumor Stem Cell Assay


  • Anticholesteremic Agents
  • FOXO3 protein, human
  • Forkhead Box Protein O3
  • Forkhead Transcription Factors
  • Intercellular Signaling Peptides and Proteins
  • Lipoproteins, HDL
  • Lipoproteins, VLDL
  • very high density lipoproteins
  • Cholesterol
  • EGFR protein, human
  • ErbB Receptors
  • Proto-Oncogene Proteins c-akt