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preclinical model (102). Furthermore, a recent follow-up report by Ellis et al. (121) also<br />
supports the idea that in <strong>ER</strong>-positive, H<strong>ER</strong>2-positive tumors, estrogen independent<br />
signaling that leads to increased proliferation is present even during therapy with AIs.<br />
Therefore, in such tumors, although estrogen deprivation may be highly effective<br />
initially, the addition of H<strong>ER</strong> signaling inhibitors may be needed for a sustained<br />
response.<br />
B. Progesterone receptor (PgR)-negativity is associated with endocrine resistance<br />
and H<strong>ER</strong> signaling<br />
Progesterone regulates cell growth in normal breast tissue and in the uterus. The PgR,<br />
which is transcriptionally upregulated as a downstream effect of activated <strong>ER</strong>, plays an<br />
important role in mammary growth and development, especially during pregnancy. Its<br />
role in breast cancer is somewhat less established than that of <strong>ER</strong>, but epidemiological,<br />
experimental, clinical, and molecular data suggest that PgR signaling plays a critical role<br />
in breast cancer development and progression (122-126). Numerous studies have<br />
identified different mechanisms of PgR activation resembling <strong>ER</strong> signaling, including<br />
ligand-dependent and ligand-independent activation (124-127). Ligand-dependent action<br />
is based on PgR functioning as a classical ligand-activated transcription factor in the<br />
nucleus (genomic action), and PgR can upregulate the expression of various genes<br />
involved in cell proliferation, survival, and tumor progression, including cyclin D1, Bcl2,<br />
and vascular endothelial growth factor (VEGF). Progesterone action is also based on<br />
PgR activating p42/44 MAPK pathways by direct interaction with c-Src-family tyrosine<br />
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