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Breast Cancer Research

, 16:R2

First Online: 09 January 2014Received: 13 June 2013Accepted: 24 December 2013DOI: 10.1186-bcr3594

Cite this article as: McCready, J., Arendt, L.M., Glover, E. et al. Breast Cancer Res 2014 16: R2. doi:10.1186-bcr3594


IntroductionThe 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.

MethodsSyngeneic 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.

ResultsASCs 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.

ConclusionsThese 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.

AbbreviationsASCadipose stromal cells

ASC-Iadipose stromal cells derived from involuting mammary glands

ASC-Ladipose stromal cells derived from lactating mammary glands

ASC-Nadipose stromal cells derived from nulliparous mammary glands

ASC-Padipose stromal cells derived from pregnant mammary glands

ASC-Radipose stromal cells derived from regressed mammary glands

BSAbovine serum albumin

CAFcarcinoma-associated fibroblast

CAF-Lcarcinoma-associated fibroblast-like

CMconditioned media

CRABP1cellular retinoic acid binding protein 1


DMEMDulbecco’s modified Eagle’s medium

FABP4fatty acid binding protein 4

GSEAgene set enrichment analysis

H and Ehemotoxylin and eosin

HSLhormone sensitive lipase

HUVEChuman umbilical cord endothelial cell

IL-6interleukin 6

KLF2Krupple-like factor 2

MHECmouse heart endothelial cell

MMP-9matrix metalloproteinase 9

NOD-SCIDnon-obese diabetic severe combined immunodeficient

PABCspregnancy-associated breast cancers

PBSphosphate-buffered saline

PDGF–Cplatelet-derived growth factor C

PlGFplacental-like growth factor

PPARγperoxisome proliferator-activated receptor gamma

Pref1preadipocyte factor 1

P-S-FPenicillan-Streptomycin, Fungicide

RMAReduction mammoplasty adipose

RT-PCRreverse transcriptase polymerase chain reaction

Sca-1stem cell antigen 1

SEMstandard error of the mean

shCrabp1small hairpin CRABP1

shScrsmall hairpin scrambled

TREthyroid response element

VEGF-Avascular endothelial growth factor A

VEGF-Cvascular endothelial growth factor C

VEGF-Dvascular endothelial growth factor D.

Electronic supplementary materialThe online version of this article doi:10.1186-bcr3594 contains supplementary material, which is available to authorized users.

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Autor: Jessica McCready - Lisa M Arendt - Eugene Glover - Vandana Iyer - Jerrica L Briendel - Stephen R Lyle - Stephen P Naber


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