Progesterone receptor-B enhances estrogen responsiveness of breast cancer cells via scaffolding PELP1- and estrogen receptor-containing transcription complexes.
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.
Departments of Medicine and Pharmacology, Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
A R
AR
Daniel
Departments of Medicine and Pharmacology, Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
A L
AL
Gaviglio
Departments of Medicine and Pharmacology, Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
T P
TP
Knutson
Department of Medicine, Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
J H
JH
Ostrander
Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN, USA.
A B
AB
D'Assoro
Department of Urology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA.
P
P
Ravindranathan
Department of Pathology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA.
Y
Y
Peng
Department of Urology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA.
G V
GV
Raj
Departments of Medicine and Pharmacology, Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
D
D
Yee
Departments of Medicine and Pharmacology, Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
C A
CA
Lange
D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology*; D002402:Cathepsin D / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D056970:Co-Repressor Proteins / Q000032:analysis / Q000502:physiology*; D004247:DNA / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000502:physiology*; D005260:Female; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D061986:MCF-7 Cells; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D017434:Protein Structure, Tertiary; D020239:Receptor Cross-Talk / Q000502:physiology; D017526:Receptor, IGF Type 1 / Q000502:physiology; D011980:Receptors, Progesterone / Q000737:chemistry / Q000502:physiology*; D013629:Tamoxifen / Q000627:therapeutic use; D014157:Transcription Factors / Q000032:analysis / Q000502:physiology*; D014158:Transcription, Genetic
D002402:Cathepsin D; D056970:Co-Repressor Proteins; D004247:DNA; D004958:Estradiol; D047628:Estrogen Receptor alpha; D007334:Insulin-Like Growth Factor I; D019869:Phosphatidylinositol 3-Kinases; D017526:Receptor, IGF Type 1; D011980:Receptors, Progesterone; D013629:Tamoxifen; D014157:Transcription Factors; C506487:ESR1 protein, human; C438485:PELP1 protein, human; C097314:progesterone receptor B; C533922:CTSD protein, human