ER ER ER ER - Endocrine Reviews

preclinical model (102). Furthermore, a recent follow-up report by Ellis et al. (121) also
supports the idea that in ER-positive, HER2-positive tumors, estrogen independent
signaling that leads to increased proliferation is present even during therapy with AIs.
Therefore, in such tumors, although estrogen deprivation may be highly effective
initially, the addition of HER signaling inhibitors may be needed for a sustained
response.
B. Progesterone receptor (PgR)-negativity is associated with endocrine resistance
and HER signaling
Progesterone regulates cell growth in normal breast tissue and in the uterus. The PgR,
which is transcriptionally upregulated as a downstream effect of activated ER, plays an
important role in mammary growth and development, especially during pregnancy. Its
role in breast cancer is somewhat less established than that of ER, but epidemiological,
experimental, clinical, and molecular data suggest that PgR signaling plays a critical role
in breast cancer development and progression (122-126). Numerous studies have
identified different mechanisms of PgR activation resembling ER signaling, including
ligand-dependent and ligand-independent activation (124-127). Ligand-dependent action
is based on PgR functioning as a classical ligand-activated transcription factor in the
nucleus (genomic action), and PgR can upregulate the expression of various genes
involved in cell proliferation, survival, and tumor progression, including cyclin D1, Bcl2,
and vascular endothelial growth factor (VEGF). Progesterone action is also based on
PgR activating p42/44 MAPK pathways by direct interaction with c-Src-family tyrosine
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