The ability of pioneer factors to respond to extracellular signals to differentiate cell type has been studied as a potential component of hormone-dependent cancers.  Hormones such as estrogen and IGFI are shown to increase pioneer factor concentration leading to a change in transcription.  Known pioneer factors such as FoxA1, PBX1, TLE, AP2, GATA factors 2/3/4, and PU.1 have been associated with hormone-dependent cancer .  FoxA1 is necessary for estrogen and androgen mediated hepatocarcinogenesis and is a defining gene for ER luminal breast cancer, as is another pioneer factor GATA3.  FOXA1 particularly is expressed in 90% of breast cancer metastases and 89% of metastic prostate cancers.  In the breast cancer cell line, MCF-7, it was found that FoxA1 was bound to 50% of estrogen receptor binding sites independent of estrogen presence.  High expression of pioneer factors is associated with poor prognosis with the exception of breast cancer where FoxA1 is associated with a stronger outcome.
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The correlation between pioneer factors and cancer has led to prospective therapeutic targeting.  In knockdown studies in the MCF-7 breast cancer cell line it was found that decreasing pioneer factors FoxA1 and AP2 decreased ER signalling.  Other fork head proteins have been associated with cancer, including FoxO3 and FoxM that repress the cell survival pathways Ras and PPI3K/AKT/IKK.  Drugs such as Paclitaxel, Imatinib, and doxorubicin which activate FoxO3a or its targets are being used.  Modification to modulate related factors with pioneer activity is a topic of interest in the early stages as knocking down pioneer factors may have toxic effects through alteration of the lineage pathways of healthy cells.