The effects of diet induced obesity on breast cancer associated pathways in mice deficient in SFRP1

Mol Cancer. 2014 May 22:13:117. doi: 10.1186/1476-4598-13-117.

Abstract

Background: Secreted frizzled-related proteins (SFRPs) are a family of proteins that block the Wnt signaling pathway and loss of Sfrp1 expression is observed in breast cancer. The molecular mechanisms by which obesity contributes to breast tumorigenesis are not well defined, but involve increased inflammation. Mice deficient in Sfrp1 show enhanced mammary gland inflammation in response to diet induced obesity (DIO). Furthermore, mammary glands from Sfrp1-/- mice exhibit increased Wnt signaling, decreased cell death responses, and excessive hyper branching. The work described here was initiated to investigate whether obesity exacerbates the aforementioned pathways, as they each play a key roles in the development of breast cancer.

Findings: Wnt signaling is significantly affected by DIO and Sfrp1-/- loss as revealed by analysis of Myc mRNA expression and active β-catenin protein expression. Furthermore, Sfrp1-/- mice fed a high fat diet (HFD) exhibit an increase in mammary cell proliferation. The death response is also impaired in the mammary gland of Sfrp1-/- mice fed a normal diet (ND) as well as a HFD. In response to γ-irradiation, mammary glands from Sfrp1-/- mice express significantly less Bax and Bbc3 mRNA, caspase-3 positive cells, and p53 protein. The expression of Wnt4 and Tnfs11 are critical for normal progesterone mediated mammary gland development and in response to obesity, Sfrp1-/- mice express significantly more Wnt4 and Tnfs11 mRNA expression. Evaluation of progesterone receptor (PR) expression showed that DIO increases the number of PR positive cells.

Conclusions: Our data indicate that the expression of Sfrp1 is a critical factor required for maintaining appropriate cellular homeostasis in response to the onset of obesity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism
  • Cell Proliferation
  • Diet, High-Fat
  • Dietary Fats / adverse effects
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Inflammation / complications
  • Inflammation / etiology
  • Inflammation / genetics*
  • Inflammation / pathology
  • Intercellular Signaling Peptides and Proteins / deficiency
  • Intercellular Signaling Peptides and Proteins / genetics*
  • Mammary Glands, Animal / metabolism
  • Mammary Glands, Animal / pathology
  • Mammary Neoplasms, Animal / complications
  • Mammary Neoplasms, Animal / etiology
  • Mammary Neoplasms, Animal / genetics*
  • Mammary Neoplasms, Animal / pathology
  • Membrane Proteins / deficiency
  • Membrane Proteins / genetics*
  • Mice
  • Mice, Knockout
  • Obesity / complications
  • Obesity / etiology
  • Obesity / genetics*
  • Obesity / pathology
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism
  • RANK Ligand / genetics
  • RANK Ligand / metabolism
  • Receptors, Progesterone / genetics
  • Receptors, Progesterone / metabolism
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism
  • Wnt Signaling Pathway
  • bcl-2-Associated X Protein / genetics
  • bcl-2-Associated X Protein / metabolism
  • beta Catenin / genetics
  • beta Catenin / metabolism

Substances

  • Apoptosis Regulatory Proteins
  • Bax protein, mouse
  • CTNNB1 protein, mouse
  • Dietary Fats
  • Intercellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Myc protein, mouse
  • PUMA protein, mouse
  • Proto-Oncogene Proteins c-myc
  • RANK Ligand
  • Receptors, Progesterone
  • Sfrp1 protein, mouse
  • Tnfsf11 protein, mouse
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • bcl-2-Associated X Protein
  • beta Catenin