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About us

Our research objectives are to elucidate the mechanisms regulating the normal development of the mammary gland and to identify genetic pathways that control the development of breast cancer. Mammary development is a fascinating process that is unique in several aspects. First, proliferation and differentiation of mammary epithelial cells occur primarily in adults. Second, mammary development is dependent upon the synergistic action of systemic hormones and local growth factors. Third, a functionally differentiated mammary gland requires a complex 3-D structure of epithelial and stromal compartments. Fourth, the mammary gland can serve as an excellent in vivo model for cell proliferation, differentiation, genome stability, and programmed cell death as it develops in defined steps during reproductive cycles.

Numerous genes have been identified that are crucial for normal mammary development and breast cancer. Their role is being studied in our research group through their deregulated expression in mammary tissue of transgenic animals and through their deletion from the mouse genome by homologous recombination. Specifically, our laboratory has the expertise to overexpress genes in a temporally and spatially controlled manner using the tet system and to delete genes in a tissue-specific and temporally controlled fashion using the Cre-loxP recombination system. Current projects include the analysis of prolactin signaling through the Jak2-Stat5 pathway, the cloning of a new mammary epithelial population from parous females, and studying the role of the Tsg101 gene during cell cycle regulation and neoplastic transformation. For more information on individual projects click <Projects> or <Funding> in the menu bar.

Accomplishments:

1997 Generation of genetically engineered mice that allow somatic gene deletions in mammary tissue [Abstract]
1998 Cloning and mapping of the mouse Tsg101 gene and revising its genomic structure in humans; many aberrant splice products, which were identified previously in cancers, are in fact alternative splice forms [Abstract]
1999 Generation of the first mouse model for a hereditary form of human breast cancer through mammary-specific deletion of the Brca1 gene (a collaboration with researchers at the NIDDK) [Abstract]
2000 Defining the role of the Bcl-x gene in erythropoiesis (Bcl-x conditional knockout) [Abstract]
2001 Discovery of a new mammary epithelial population in parous animals (PI-MECs), which has certain features of pluripotent mammary stem cells [Abstract]
2002 Defining the biological role of Tsg101 in vivo (conventional and mammary-specific knockout); Tsg101 is essential for cell proliferation and cell survival; however, in contrast to previous reports Tsg101 is not a primary tumor suppressor gene for sporadic forms of breast cancer [Abstract]
2004 Defining the role of Jak2 during mammary development (Jak2 conditional knockout) [Abstract #1] [Abstract #2]
Parity-induced mammary epithelial cells (PI-MECs) facilitate tumorigenesis in selected transgenic mouse models. [Abstract]
Discriminating the p53-dependent and p53-independent mechanisms for cell cycle arrest and cell death in cells deficient in Tsg101 [Abstract]
2005 Expression of the Whey Acidic Protein (Wap) is necessary for adequate nourishment of the offspring but not functional differentiation of mammary epithelial cells [Abstract]
2007 Parity-induced mammary epithelial cells (PI-MECs) are multipotent and express cell surface markers associated with stem cells [Abstract]
Tsg101 is upregulated in a subset of invasive human breast cancers and its targeted overexpression in transgenic mice reveals weak oncogenic properties for mammary cancer initiation [Abstract]
The Janus kinase 2 (Jak2) is required for expression and nuclear accumulation of Cyclin D1 in proliferating mammary epithelial cells [Abstract]
2009 Generation of Wap-rtTA knockin mice that allow a ligand-inducible expression of transgenes in the mammary gland [Abstract]
2010

Jak2 is required for the initiation but not maintenance of ErbB2 (Her2/neu) and prolactin-induced mammary cancer [Abstract #1] [Abstract #2]
Generation of a novel mouse strain that permits a temporally and spatially controlled expression of responder genes in embryonic and multiple adult tissues [Abstract]
2011 Broad targeting of cyclin D functions may be essential for effective treatment of ErbB2-induced breast cancers due to functional cross compensation between cyclin D isoforms [Abstract].

 

Animal Models Generated:

Official Strain Nomenclature MGI Accession ID
Tg(Wap-cre)11738Mam 2176164 click here to order (or click here for NCI)
Tg(MMTV-cre)1Mam (A-line) 2176162 click here to order
Tg(MMTV-cre)4Mam (D-line) 2176163 click here to order
Tg(MMTV-cre)22Mam (F-line) 3802641 click here to order
Tsg101tm1Kuw 2447442
Tsg101tm1.1Kuw 2447444
Jak2tm1Kuw 3045140
Jak2tm1.1Kuw 3045147 click here to order
Waptm1Kuw 3584430 click here to order
Waptm2(rtTA)Kuw 3799057
Tg(Wap-Tsg101)4389Kuw 3710126 click here to order
Tg(CAG-bGeo,-tTA,-EGFP)2A11Kuw 3849835
Tg(MMTV-tTA)25754Kuw 5300554
Tg(MMTV-tTA)25755Kuw 5300555
Tg(tetO-Ccnd1*T286A,-luc)10897Kuw 5300556
Tg(tetO-Ccnd1*T286A,-luc)11233Kuw 5300557
Tg(tetO-Stat5a*S710F,-luc)11651Kuw 5300597

Tg(tetO-Stat5a*S710F,-luc)11676Kuw

 5300600

 

Special recognition of our work in scientific journals, web sites, newspapers, and radio:

“UNMC breast cancer researcher pushes science forward with his research”, interview with KIOS 91.5FM, February 20, 2012

“Dr. Wagner-led study yields novel breast cancer finding” UNMC News, January 24, 2012

“Cyclin D3 compensates for the loss of Cyclin D1 during ErbB2-induced mammary tumor initiation and progression.” MMHCC Newsletter, December 2011
This publication has been selected and evaluated by J Alan Diehl, a Member of the Faculty of 1000 (F1000), which places this work in F1000 library of the top 2% of published articles in biology and medicine.

“New ‘Knock-Out’ Gene Model Provides Molecular Clues to Breast Cancer” MMHCC Newsletter, October 2007

"Mammary Gland Cells Formed During Maternity Have Stem Cell Properties" NCI News Release, Dec. 6, 2004 [PDF]

"Parity-induced mammary epithelial cells promote tumor growth in transgenic mice" Health & Medicine Week, November 22, 2004, page 142 (Health & Medicine Week and Cancer Weekly via NewsRx.com ) [HTML]

"TSG101: An Antiviral Target with a Murky Past" in The Scientist 18[1]:24, Jan. 19, 2004 [PDF]

"A Pregnancy-Induced Stem Cell: Is it the clue to pregnancy's anti-cancer effects?" in the Press Book of the 42ND ANNUAL MEETING of THE AMERICAN SOCIETY FOR CELL BIOLOGY, December 14-18, 2002 [PDF]

"Refining Transgenic Mice: Emerging technologies allow researchers to make tissue- and developmental stage-specific knockouts" in The Scientist 16[13]:34, Jun. 24, 2002 [HTML]

"NIH Animal Model Uncovers a Role of BRCA1-Associated Breast Tumor Formation" NIDDK News Release [HTML]

"Branching out with BRCA1" in Nature Genetics 22: 10, May 1,1999 [PDF]

"New Model for Hereditary Breast Cancer" in Science 284: 723-725, Issue of 30 Apr 1999 [HTML]

"Research Shows Role of a Gene In Breast Cancer" in The Wall Street Journal, 04/30/1999 [HTML]

"Gene May Hold Cancer Clues" in Newsday, 04/30/1999 ppA32 [HTML]

"Wie erblicher Brustkrebs entsteht (German)" in a Press Release of the German Research Foundation (DFG), 04/30/1999, and in Informationsdienst Wissenschaft, 04/30/1999 [HTML] [HTML2]

"The Origins Of Hereditary Breast Cancer - Studies With Knock-Out Mice Reveal Underlying Mechanisms" in EurekAlert!, 04/30/1999 [HTML]

"Offenbar wirkt das intakte Gen wie ein Tumorsuppressor-Gen: So trägt BRCA1 zum Entstehen von Brustkrebs bei (German)" in ÄrzteZeitung, 8.6.1999 [HTML]

"Oxytocin and Mammary Gland Development" Newsletter of the UK Genetical Society, No. 36, May 1998 [HTML]