title: Pregnancy-associated breast cancers are driven by differences in adipose stromal cells present during lactation.
abstract: BACKGROUND
  The prognosis of breast cancer is strongly influenced by the developmental stage of the breast when the tumor is diagnosed. Pregnancy-associated breast cancers (PABCs), cancers diagnosed during pregnancy, lactation, or in the first postpartum year, are typically found at an advanced stage, are more aggressive and have a poorer prognosis. Although the systemic and microenvironmental changes that occur during post-partum involution have been best recognized for their role in the pathogenesis of PABCs, epidemiological data indicate that PABCs diagnosed during lactation have an overall poorer prognosis than those diagnosed during involution. Thus, the physiologic and/or biological events during lactation may have a significant and unrecognized role in the pathobiology of PABCs.
  
  
  METHODS
  Syngeneic in vivo mouse models of PABC were used to examine the effects of system and stromal factors during pregnancy, lactation and involution on mammary tumorigenesis. Mammary adipose stromal cell (ASC) populations were isolated from mammary glands and examined by using a combination of in vitro and in vivo functional assays, gene expression analysis, and molecular and cellular assays. Specific findings were further investigated by immunohistochemistry in mammary glands of mice as well as in functional studies using ASCs from lactating mammary glands. Additional findings were further investigated using human clinical samples, human stromal cells and using in vivo xenograft assays.
  
  
  RESULTS
  ASCs present during lactation (ASC-Ls), but not during other mammary developmental stages, promote the growth of carcinoma cells and angiogenesis. ASCs-Ls are distinguished by their elevated expression of cellular retinoic acid binding protein-1 (crabp1), which regulates their ability to retain lipid. Human breast carcinoma-associated fibroblasts (CAFs) exhibit traits of ASC-Ls and express crabp1. Inhibition of crabp1in CAFs or in ASC-Ls abolished their tumor-promoting activity and also restored their ability to accumulate lipid.
  
  
  CONCLUSIONS
  These findings imply that (1) PABC is a complex disease, which likely has different etiologies when diagnosed during different stages of pregnancy; (2) both systemic and local factors are important for the pathobiology of PABCs; and (3) the stromal changes during lactation play a distinct and important role in the etiology and pathogenesis of PABCs that differ from those during post-lactational involution.
authors.forename: Jessica
authors.initials: J
authors.lastname: McCready
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Arendt
authors.forename: Eugene
authors.initials: E
authors.lastname: Glover
authors.forename: Vandana
authors.initials: V
authors.lastname: Iyer
authors.forename: Jerrica L
authors.initials: JL
authors.lastname: Briendel
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Lyle
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Naber
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Jay
authors.forename: Charlotte
authors.initials: C
authors.lastname: Kuperwasser
mesh_terms: D016475:3T3 Cells; D017667:Adipocytes / Q000166:cytology* / Q000378:metabolism; D000273:Adipose Tissue / Q000166:cytology* / Q000378:metabolism; D000818:Animals; D001943:Breast Neoplasms / Q000473:pathology*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology; D005260:Female; D005347:Fibroblasts / Q000166:cytology; D006801:Humans; D007774:Lactation; D050356:Lipid Metabolism; D008321:Mammary Glands, Animal / Q000166:cytology / Q000473:pathology*; D015674:Mammary Neoplasms, Animal / Q000401:mortality / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D011247:Pregnancy; D011379:Prognosis; D018168:Receptors, Retinoic Acid / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D017154:Stromal Cells / Q000166:cytology / Q000378:metabolism; D014183:Transplantation, Heterologous
chemical_list: D018168:Receptors, Retinoic Acid; C082927:retinoic acid binding protein I, cellular