Lipoprotein(a) and vitamin C impair development of breast cancer tumors in Lp(a)+; Gulo-/- mice

Int J Oncol. 2016 Sep;49(3):895-902. doi: 10.3892/ijo.2016.3597. Epub 2016 Jul 1.


Cancer progression is characterized by loss of extracellular matrix (ECM) integrity, which is a precondition for tumor growth and metastasis. In order to elucidate the precise mechanisms of ECM degradation in cancer we used a genetically modified mouse mimicking two distinct human metabolic features associated with carcinogenesis, the lack of endogenous vitamin C synthesis and the production of human Lp(a). Female Lp(a)+; Gulo(-/-) and control wild-type Balb/c mice without these two metabolic features were orthotopically inoculated with 4T1 breast cancer cells (5x105). The transgenic and control mice were divided into 4 different dietary groups in respect to dietary vitamin C intake: i) low ascorbate intake for 6 weeks; ii) high ascorbate intake for 6 weeks; iii) low ascorbate intake for 3 weeks followed by high ascorbate for 3 weeks; iv) high ascorbate intake for 3 weeks followed by low ascorbate for 3 weeks. After 6 weeks, all wild-type mice developed tumors. In contrast, Lp(a)+; Gulo(-/-) mice developed one third less primary tumors (low ascorbate diet) or no primary tumors at all (high ascorbate diet). Significantly, tumors from Lp(a)+; Gulo(-/-) mice immunostained positively for Lp(a) and their size was inversely proportional to Lp(a) serum levels. The results implicate that Lp(a) may play a role in controlling tumor growth and expansion. The most likely mechanism is the competitive inhibition of plasmin-induced ECM degradation due to the homology of Lp(a) components to plasminogen. The confirmation of this pathomechanism could lead to a universal therapeutic target for the prevention and treatment of cancer.

MeSH terms

  • Animals
  • Apolipoproteins A / blood
  • Apolipoproteins A / genetics*
  • Apolipoproteins B / blood
  • Apolipoproteins B / genetics*
  • Ascorbic Acid / administration & dosage*
  • Cell Line, Tumor
  • Extracellular Matrix / drug effects
  • Female
  • Humans
  • Lipoprotein(a) / deficiency*
  • Mammary Neoplasms, Experimental / blood
  • Mammary Neoplasms, Experimental / genetics
  • Mammary Neoplasms, Experimental / prevention & control*
  • Mice
  • Mice, Transgenic


  • Apolipoproteins A
  • Apolipoproteins B
  • Lipoprotein(a)
  • Ascorbic Acid