title: The effects of diet induced obesity on breast cancer associated pathways in mice deficient in SFRP1.
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.
  
  
  RESULTS
  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.
authors.forename: Kelly J
authors.initials: KJ
authors.lastname: Gauger
authors.forename: Lotfi M
authors.initials: LM
authors.lastname: Bassa
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Henchey
authors.forename: Josephine
authors.initials: J
authors.lastname: Wyman
authors.forename: Jennifer
authors.initials: J
authors.lastname: Ser-Dolansky
authors.forename: Akihiko
authors.initials: A
authors.lastname: Shimono
authors.affiliation: Pioneer Valley Life Sciences Institute, Baystate Medical Center, 3601 Main St, Springfield, MA 01199, USA. sallie.schneider@baystatehealth.org.
authors.forename: Sallie S
authors.initials: SS
authors.lastname: Schneider
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D059305:Diet, High-Fat; D004041:Dietary Fats / Q000009:adverse effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007249:Inflammation / Q000150:complications / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D036341:Intercellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics*; D008321:Mammary Glands, Animal / Q000378:metabolism / Q000473:pathology; D015674:Mammary Neoplasms, Animal / Q000150:complications / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000150:complications / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism; D011980:Receptors, Progesterone / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D060449:Wnt Signaling Pathway; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism; D000094742:Secreted Frizzled-Related Proteins
chemical_list: D051017:Apoptosis Regulatory Proteins; D004041:Dietary Fats; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D016271:Proto-Oncogene Proteins c-myc; D053245:RANK Ligand; D011980:Receptors, Progesterone; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D051028:bcl-2-Associated X Protein; D051176:beta Catenin; C494827:Bax protein, mouse; C495267:CTNNB1 protein, mouse; C489428:Myc protein, mouse; C488588:PUMA protein, mouse; C485539:Sfrp1 protein, mouse; D000094742:Secreted Frizzled-Related Proteins; C505689:Tnfsf11 protein, mouse