FOXC1 Cancer | My Site

What is FOXC1?

FOXC1 is a forkhead-box (C1) Transcription Factor (TF) protein which control gene activity by binding to specific DNA sequences, thereby regulating when, how and how much genes are turned on or off. FOXC1 is a mesenchymal lineage driver normally involved in embryonic development and in maintaining adult tissue-specific cell populations. In certain cancers, particularly Triple-Negative Breast Cancer (TNBC), FOXC1 becomes dysregulated and overexpressed.

FOXC1 is a proven independent predictor of metastatic propensity and heightened risk of cancer recurrence at the time of initial diagnosis. The presence of FOXC1 in cancer cells identifies within the tumor landscape, EMT-activated aggressive cancer cells with high metastatic propensity and poor prognosis. Historically eluding detection, VERESCA FOXC1 IHC Precision Oncology Test revolutionizes the cancer diagnosis allowing pathologists to analyze the tumor landscape (tumor proportion and progression intensity) for aggressive FOXC1+ pro-metastatic cancer cell subpopulations co-existing in primary tumors. FOXC1+ tumor cells are resistant to many standard-of-care therapies (i.e. endocrine therapy) and oncologists are now able to design more effective treatment mitigating disease recurrence.

What Activates FOXC1?

Multiple Cellular Pathways Regulate FOXC1:

Signal Transduction Pathways

Epidermal Growth Factor Receptor (EGFR), Receptor Tyrosine Kinases (RTK), Cytokines, Hypoxia and other signal transduction pathways converge upon the NFkB-FOXC1 axis.

Epithelial-Mesenchymal Transition (EMT)

EMT enables cancer cells to depart from the primary tumor, invade surrounding tissue, and disseminate to distant organs. FOXC1 is activated during the initial stages of EMT and modulates cell fate to a highly aggressive, invasive, mesenchymal lineage.

Loss of Tumor Suppressor Function

GATA3 protein, an important activator of Estrogen Receptor, together with BRCA1 tumor suppressor protein binds to the FOXC1 promoter co-repressing FOXC1. This co-repression is lost with non-functional BRCA1 mutations in basal-like breast cancer (BLBC).

FOXC1-NFKB Positive Feedback Loop

Positive feedback loop between FOXC1 <----> NFKB downstream at the convergence of many estrogen independent signal transduction pathways bypasses upstream signaling and may reduce benefits from upstream targeted therapies.

Estrogen Receptor indirectly suppresses FOXC1 activation

ER suppresses activation of TGF-B and NFkB, core upstream activators of FOXC1. ER is a master regulator suppressing EMT core initiating factors.

Super Enhancer Driven FOXC1 Activation, Auto-Regulation and Core Regulatory Circuit (CRC)

In TNBC, FOXC1 may bind to Super Enhancers in its own regulatory region, thus providing a positive feedback loop where FOXC1 reinforces its own expression and interacts with other transcription factors to form a core regulatory circuit sustaining high expression levels required to maintain an aggressive, invasive, metastatic phenotype.

FOXC1 non-canonically activates genes (i.e., Wnt, Notch, Hedgehog) which further activates EMT core transcription factors.
EMT core factors (i.e., Snail, Slug, Zeb1) suppress ER activation and ER signaling abrogating ER suppressive effects on EMT.
Competitive binding of FOXC1 at the ER promoter blocks GATA3 ER activation, silencing ER activation.

FOXC1 Modulates a Core Regulatory Circuit (CRC) Driving Proliferation, EMT, Invasion, Metastasis, and Chemoresistance

FOXC1 regulates cell fate driving major gene networks involved in invasion and metastasis.

FOXC1 and its downstream network require sustained activation to maintain cellular identity. A core regulatory circuit (CRC) in cancer is a network of transcription factors (TFs) and super-enhancers (SEs) that maintain a cancer cell's specific gene expression and identity. These TFs are self-regulating and cross-regulate each other through feed-forward loops, binding to SEs to control the expression of lineage-specific genes. FOXC1 drives invasion and metastasis in the FOXC1 CRC:

Sustained high level expression of FOXC1 is central to the oncogenic role driving aggressive features of growth, metastasis and chemoresistance.
Key cofactors and interacting partners (NR2F2, epigenetic regulators)
Major downstream signal pathways (Wnt, NF-κB, MMP, FGFR1)
Migration and metastasis (CXCR4)
Angiogenesis (VEGF)
Proliferation (cMYC, Cyclin D1)
Dormancy (Hair Follicle Stem Cell, Bone Marrow Stem Cells)

®