FosB is highly expressed in normal mammary epithelia, but downregulated in poorly differentiated breast carcinomas.

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FosB is highly expressed in normal mammary epithelia, but down-regulated in poorly differentiated breast carcinomas. Karin Milde-Langosch, Holger Kappes, Sabine Riethdorf, Thomas Löning, and Ana-Maria BambergerHamburg Medical School. Breast Cancer Res Treatm 77: 265-75 (2003)

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FosB belongs to the AP-1 (activating protein 1) transcription factors c-jun junB Jun family junD c-fos fosB Fos family fra-1 fra-2 AP-1

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c-Jun JunB JunD c-Fos FosB Fra-1 Fra-2 Jun - Jun or Jun - Fos * “AP-1 activity“ depends on: target gene (promoter sequence) abundance of single AP-1 proteins in the cell interaction with other TF / cofactors activation of TF by phosphorylation *TRE = TPA-responsive element FosB dimerizes with Jun proteins and binds to TRE* elements in promoter / enhancer regions of target genes

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AP-1 proliferation: Cyclin D1, Rb, p16 etc. hypoxia: CYP2J2 angiogenesis: VEGF metastasis: CD44, osteopontin, KAI-1 etc. apoptosis: BCl-2, BCl-Xl, FasL etc. invasion: MMP‘s, uPA, PAI-1, uPAR, TIMP-1 etc. differentiation: ER, myogenin, involucrin etc. AP-1 proteins : regulators of tumor growth and progression

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FosB expression in breast cancer

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Expression von AP-1 proteins in mammary cell lines Strong FosB expression in the ER-positive T47D (and MCF7) cells,FosB-negative results in ER-negative HBL100 and MDA-MB231 cells!

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Expression of AP-1 proteins in breast cancer (n=68) (Western blots) Striking differences in FosB expression between mammary tumors

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Tu in situ- hybridization immunohisto- chemistry Fos B expression in normal mammary glands and breast cancer Fos B is expressed in normal mammary epithelia, but down-regulated in poorlydifferentiated carcinomas ! A, D (right), E: normal mammary glands and ducts; B, C, D (left), F: mammary carcinomas

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FosB-Expression FosB expression* in mammary carcinomas correlates with estrogen receptor (ER) status *FosB expression determined by immunohistochemistry (IHC) FosB-positive tumors are mostly ER-positive carcinomas! p<0,001

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FosB expression* in mammary carcinomas correlates with estrogen receptor (ER) status FosB-positive tumors are mostly well-differentiated carcinomas!

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How is FosB down-regulated in mammary carcinomas? 1. Mutation? No mutation found in all exons of 17 mammary carcinomas and 3 breast cancer cell lines. But: missense mutation in HBL-100 cells. 2. Transcriptional regulation? semiquantitative RT-PCR: weak association of FosB protein and mRNA expression. FosB expression in mammary carcinoma is partly regulated at a transcriptional level.

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Resumée FosB is expressed in normal mammary epithelia and might be associated withdifferentiation in mammary tumor cells. 2. Loss of FosB expression might be involved in dedifferentiation of tumor cells and might represent a negative prognostic factor.

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	milde@uke.uni-hamburg.de 4 Years ago.



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