Ltbp1Lis focally induced in embryonic mammary mesenchyme, demarcates the ductal luminal lineage and is upregulated during involutionReportar como inadecuado

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Breast Cancer Research

, 15:R111

First Online: 21 November 2013Received: 18 March 2013Accepted: 31 October 2013DOI: 10.1186-bcr3578

Cite this article as: Chandramouli, A., Simundza, J., Pinderhughes, A. et al. Breast Cancer Res 2013 15: R111. doi:10.1186-bcr3578


IntroductionLatent TGFβ binding proteins LTBPs govern TGFβ presentation and activation and are important for elastogenesis. Although TGFβ is well-known as a tumor suppressor and metastasis promoter, and LTBP1 is elevated in two distinct breast cancer metastasis signatures, LTBPs have not been studied in the normal mammary gland.

MethodsTo address this we have examined Ltbp1 promoter activity throughout mammary development using an Ltbp1L-LacZ reporter as well as expression of both Ltbp1L and 1S mRNA and protein by qRT-PCR, immunofluorescence and flow cytometry.

ResultsOur data show that Ltbp1L is transcribed coincident with lumen formation, providing a rare marker distinguishing ductal from alveolar luminal lineages. Ltbp1L and Ltbp1S are silent during lactation but robustly induced during involution, peaking at the stage when the remodeling process becomes irreversible. Ltbp1L is also induced within the embryonic mammary mesenchyme and maintained within nipple smooth muscle cells and myofibroblasts. Ltbp1 protein exclusively ensheaths ducts and side branches.

ConclusionsThese data show Ltbp1 is transcriptionally regulated in a dynamic manner that is likely to impose significant spatial restriction on TGFβ bioavailability during mammary development. We hypothesize that Ltbp1 functions in a mechanosensory capacity to establish and maintain ductal luminal cell fate, support and detect ductal distension, trigger irreversible involution, and facilitate nipple sphincter function.

AbbreviationsARAndrogen receptor

BACBacterial artificial chromosome

BMPBone morphogenetic protein

BpBase pairs

CDCluster of differentiation


ECMExtracellular matrix

EDTAEthylenediaminetetraacetic acid

EGFEpidermal growth factor

EMTEpithelial to mesenchymal transition

EREstrogen receptor

ESEmbryonic stem

FAM6-carboxyfluorescein FAM


FDGFluorescein Di-β-D-Galactopyranoside


HRPHorseradish peroxidase


LAPLatency-associated propeptide

Lef1Lymphoid enhancer-binding factor 1

LLCLarge latent complex

LTBPLatent TGFβ binding protein

MGBDihydrocyclopyrroloindole tripeptide minor groove binder

NFRNuclear fast red

PABCPregnancy-associated breast cancer

PBSPhosphate buffered saline


qRT-PCRQuantitative reverse transcriptase-polymerase chain reaction

RERRough endoplasmic reticulum

RGDArginine-glycine-aspartic acid

Sca1Stem cell antigen 1

SLCSmall latent complex

SMASmooth muscle actin

SPSignal peptide

TEBTerminal end bud

TGFβTransforming growth factor β

TGF-βRTransforming growth factor β Receptor


Electronic supplementary materialThe online version of this article doi:10.1186-bcr3578 contains supplementary material, which is available to authorized users.

Anupama Chandramouli, Julia Simundza, Alicia Pinderhughes contributed equally to this work.

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