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It is the ability to metastasize that ultimately makes breast
cancer a fatal disease. Metastatic cells are often characterized as
having undergone an epithelial to mesenchymal transition (EMT). EMT
is a common feature of both embryonic development and invasive
tumors where epithelial cells dedifferentiate to a more
fibroblast-like state and regain the ability to invade, migrate,
and/or proliferate in an uncontrolled fashion. Mayny studies have
sought to define the genes and signaling pathways that underlie the
conversion to EMT and metastasis in breast cancer. Much less
emphasis has been placed on identifying the transcription factors
that ultimately control this process.
We have recently developed a new model for EMT in human breast
cancer involving the transcription factor CCAAT/Enhancer Binding
Protein (C/EBP)beta. C/EBPbeta is critical for growth and
differentiation of the mammary gland. Increased mammary epithelial
cell proliferation, migration, and branching during puberty or
early pregnancy and differentiation at late pregnancy are severely
impaired in C/EBPbeta null mice which fail to lactate. 3 isoforms
of C/EBPbeta can be produced in cells via alternative translation
initiation at 3 in-frame methionines. C/EBPbeta-1 and beta-2 are
transactivators, and differ by only 23 N-terminal amino acids
present in beta-1 but not beta-2. C/EBPbeta-3, lacks the N-terminal
half of C/EBPbeta including the transactivation domain, and
therefore represses transcription. C/EBPbeta-1 is the only isoform
present in normal tissue from reduction mammoplasty. However, 70%
of invasive surgical primary breast tumor samples have acquired a
high level of C/EBPbeta-2 expression, and C/EBPbeta-2 is the only
transactivator isoform expressed in breast cancer cell lines.
Although it was first assumed that C/EBPbeta-1 and ¿2 would be
functionally redundant transactivators because of their extensive
similarity, their different expression patterns suggest otherwise.
In fact, MCF10A normal human mammary epithelial cells
overexpressing C/EBPbeta-2, but not C/EBPbeta-1, undergo EMT and
acquire an invasive phenotype. MCF10A C/EBPbeta-2 cells are
anchorage-independent, form foci in soft agar, show loss of
junctional E cadherin localization, exhibit cytoskeletal
reorganization with actin stress fibers typical of motile
fibroblasts, express vimentin, and are invasive in vitro.
From these and other studies we propose that C/EBPbeta-1 and -2
govern different phases of mammary gland development. C/EBPbeta-1
may be required for terminal differentiation during late pregnancy
and lactation (likely activating milk protein genes), whereas
ductal epithelial outgrowth and invasion through the stromal fat
pad during puberty is the dominion of C/EBPbeta-2. Abberant
C/EBPbeta-2 expression during cancer progression may activate a
genetic program of motility and invasion in breast tumor cells.
Currently, we are extending our studies into animal models. We are
evaluating if expression of C/EBPbeta-2 in breast cancer cell lines
that are not invasive (MCF7, BT20) will cause the cells to undergo
EMT and metastasize once implanted as xenografts in the mammary
gland. We have also generated mice carrying an MMTV-driven
C/EBPbeta -2 transgene; virgin females exhibit precocious,
hyperplastic mammary gland development whereas multiparous females
develop tumors. We will continue to study these animals to
determine if females show accelerated development of metastatic
carcinoma when crossed with other mouse models of breast cancer.
Understanding the transcription factors responsible for metastatic
capability, of which C/EBPbeta-2 is an enticing candidate, will
accelerate the design of molecularly-targeted therapies capable of
slowing or halting the often fatal spread of breast cancer to
secondary sites.
Publications
The following timeline graph is generated from all co-authored publications.
Featured publications are shown below:
- C/EBPβ's role in determining Ras-induced senescence or transformation. Atwood AA, Sealy LJ (2011) Small GTPases 2(1): 41-46
› Primary publication · 21686281 (PubMed) · PMC3116617 (PubMed Central) - Genomic profiling of C/EBPβ2 transformed mammary epithelial cells: a role for nuclear interleukin-1β. Russell A, Boone B, Jiang A, Sealy L (2010) Cancer Biol Ther 10(5): 509-19
› Primary publication · 21057224 (PubMed) · PMC3040973 (PubMed Central) - The C/EBPbeta isoform, liver-inhibitory protein (LIP), induces autophagy in breast cancer cell lines. Abreu MM, Sealy L (2010) Exp Cell Res 316(19): 3227-38
› Primary publication · 20699097 (PubMed) · PMC2967436 (PubMed Central)