Progesterone and
estrogen are important drivers of
breast cancer proliferation. Herein, we probed
estrogen receptor-α (ER) and
progesterone receptor (PR) cross-talk in
breast cancer models. Stable expression of PR-B in PR-low/ER+ MCF7 cells increased cellular sensitivity to
estradiol and
insulin-like growth factor 1 (IGF1), as measured in growth assays performed in the absence of exogenous
progestin; similar results were obtained in PR-null/ER+ T47D cells stably expressing PR-B. Genome-wide microarray analyses revealed that unliganded PR-B induced robust expression of a subset of
estradiol-responsive ER target genes, including
cathepsin-D (CTSD).
Estradiol-treated MCF7 cells stably expressing PR-B exhibited enhanced ER Ser167 phosphorylation and recruitment of ER, PR and the
proline-,
glutamate- and
leucine-rich
protein 1 (PELP1) to an
estrogen response element in the CTSD distal promoter; this complex co-immunoprecipitated with IGF1 receptor (IGFR1) in whole-cell lysates. Importantly, ER/PR/PELP1 complexes were also detected in human
breast cancer samples. Inhibition of IGF1R or
phosphoinositide 3-kinase blocked PR-B-dependent CTSD
mRNA upregulation in response to
estradiol. Similarly, inhibition of IGF1R or PR significantly reduced ER recruitment to the CTSD promoter. Stable knockdown of endogenous PR or
onapristone treatment of multiple unmodified
breast cancer cell lines blocked
estradiol-mediated CTSD induction, inhibited growth in soft
agar and partially restored
tamoxifen sensitivity of resistant cells. Further, combination treatment of
breast cancer cells with both
onapristone and IGF1R
tyrosine kinase inhibitor AEW541 was more effective than either agent alone. In summary, unliganded PR-B enhanced proliferative responses to
estradiol and IGF1 via scaffolding of ER-α/PELP1/IGF1R-containing complexes. Our data provide a strong rationale for targeting PR in combination with ER and IGF1R in patients with
luminal breast cancer.