ER ER ER ER - Endocrine Reviews

kinases, an event that requires progesterone binding to PgR and occurs in the cytoplasm
and/or in association with cell membranes (non-genomic or MISS action) (124, 127).
Intriguing preclinical and clinical studies have recently suggested that PgR-negativity in
ER-positive breast cancer may be a marker of hyperactive growth factor signaling (128)
rather than a result of a non-functional ER signaling pathway, as previously suggested
(129) . Recent laboratory studies suggest that growth factors in the IGF and EGF families
that activate the PI3K-AKT-mTOR pathway can reduce expression of PgR at its
transcriptional (mRNA) level (129). Alternatively, studies from Lange and associates
(130, 131) have demonstrated a coupling between transcriptional hyperactivity of PgR
and increased PgR protein turnover. Accordingly, HER downstream kinases, such as
p42/44 MAPK and Cyclin dependent kinase 2 (CDK2), which phosphorylate PgR and its
accessory proteins and dramatically increase PgR transcriptional activity including in the
presence of low levels of progesterone, also greatly increase PgR turnover, resulting in
PgR-low or PgR-negative tumors (128, 129, 132-135). Finally, increased ligand-
independent activation and transcriptional hypersensitivity of PgR associated with breast
cancer cell growth have also been recognized as deriving from the phosphorylation of
PgR under EGFR/EGF signaling (134).
These molecular data, in concert with clinical findings that follow, suggest that loss of
PgR expression in some tumors, at the mRNA and/or the protein level, may be due to
increased growth factor receptor activity potentially leading to endocrine therapeutic
resistance. Although more studies are needed on this topic, these results suggest that
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