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Briegel Lab

Molecular mechanisms of mammary gland development and breast carcinogenesis

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Investigator / Contact Person Karoline Briegel

Research

Dr. Briegel’s laboratory has pioneered the discovery of LBH (Limb-Bud-and-Heart) (1), a novel transcriptional cofactor in the oncogenic WNT signaling pathway (2), that forms its own protein class (3). They identified in genetic mouse models in vivo that LBH is a key controller of mammary stem cell self-renewal/maintenance and basal mammary epithelial lineage specification (4,5). They also showed LBH represses luminal lineage differentiation, notably, expression of luminal differentiation marker, estrogen hormone receptor alpha (ER) (5). Significantly, Dr. Briegel’s team found that in breast cancer, LBH is selectively overexpressed in poor prognosis, basal-like triple-negative breast cancers (TNBC), correlating with WNT pathway hyperactivation and poor outcome. TNBC are highly aggressive, lethal breast cancers, most commonly diagnosed in young and African-American women, that lack specific treatment options due to their triple negativity for expression of key targetable markers, Estrogen Receptor, Progesterone Receptor, and HER2. Their work highlights LBH as a promising new biomarker and molecular target for this difficult-to-treat breast disease. Current research focuses on identifying the potential causal role of LBH in the etiology of basal-subtype TNBC and in WNT-mediated cancer stem cell transformation.

A second research interest of her laboratory is to identify molecular drivers of the epithelial-mesenchymal transition (EMT), a key initiation step in metastasis. EMT is a morphogenetic program responsible for increased epithelial cell plasticity and cell motility during embryonic development, but when deregulated in cancer promotes the invasion and dissemination of primary epithelial tumor cells. She first identified that TBX2 (T box 2), a developmentally important transcription factor and putative immortalizing oncogene, is a potent novel inducer of EMT in breast cancer (6). TBX2 is preferentially amplified in BRCA1/2-deficient and high-grade sporadic breast cancers, as well as in a variety of other aggressive cancer types (e.g., pancreatic, skin, colon cancer). She has established primary EMT tissue culture model systems using human mammary epithelial cells (7) and a transgenic mouse model that will allow them to further dissect the EMT transcriptional program during breast carcinogenesis.

Relevant references

  1. Briegel, KJ, and Joyner, AL, Identification, and characterization of Lbh, a novel conserved nuclear protein expressed in early limb and heart development, Developmental Biology 233: 291-304, 2001. PMID: 11336496
  2. Rieger, ME, Sims, AH, Coats, ER, Clarke, RB, and Briegel, KJ, The embryonic transcription cofactor LBH is a target of the WNT signaling pathway in epithelial development and in aggressive basal subtype breast cancers, Molecular Cell Biology. 30: 4267-4279, 2010. PMID: 20606007 
  3. Al-Ali, H, Rieger, ME, Seldeen, KL, Harris, TK, Farooq, A, and Briegel, KJ, Biophysical characterization reveals structural disorder in the developmental transcriptional regulator LBH, Biochem Biophys Res Commun. 391: 1104-1109, 2010. PMID: 20005203. 
  4. Lindley LE, and Briegel KJ, Generation of mice with a conditional Lbh null allele. Genesis 51 (7): 491-497, 2013. PMID: 23495064. 
  5. Lindley LE, Curtis KM, Sanchez-Mejias A, Rieger ME, Robbins DJ, and Briegel KJ, The WNT-controlled transcriptional regulator LBH is required for mammary stem cell expansion and maintenance of the basal lineage, Development 142 (5): 893-904, 2015. PMID: 25655704.
  6. Wang B, Lindley LE, Fernandez-Vega V, Rieger ME, Sims AH, Briegel KJ, The T Box Transcription Factor TBX2 Promotes Epithelial-Mesenchymal Transition and Invasion of Normal and Malignant Breast Epithelial Cells. PLoS ONE 7 (7): e41355, 2012. PMID: 22844464
  7. Lindley, LE, and Briegel, KJ, Molecular characterization of TGF beta-induced epithelial mesenchymal transition of finite life-span human mammary epithelial cells. Biochem Biophys Res Commun 399 (4): 659-664, 2010. PMID: 20691661