Summary Hormone signaling is important in a number of disease states, and hormone receptors are effective therapeutic targets. PGRMC1 (progesterone receptor membrane component 1) is a member of a multi-protein complex that binds to progesterone and other steroids, as well as pharmaceutical compounds. In spite of its name, PGRMC1 shares homology with cytochrome b5-related proteins rather than hormone receptors, and heme binding is the sole biochemical activity of PGRMC1. PGRMC1 and its homologues regulate cholesterol synthesis by activating the P450 protein Cyp51/lanosterol demethylase, and the cholesterol synthetic pathway is an important target in cardiovascular disease and in treating infections. PGRMC1 binding partners include multiple P450 proteins, PAIR-BP1, Insig, and an uncharacterized hormone/drug-binding protein. PGRMC1 is induced in a spectrum of cancers, where it promotes cell survival and damage resistance, and PGRMC1 is also expressed in the nervous system and tissues involved in drug metabolism, cholesterol synthesis and hormone synthesis and turnover. One of the appealing features of PGRMC1 and its associated protein complex is its affinity for steroids and drugs. Together with its biological role in promoting tumor survival, PGRMC1 is an attractive target for therapeutic intervention in cancer and related malignancies.

Tumorigenesis requires the concerted action of multiple pathways, including pathways that stimulate proliferation and increase metabolism. Progesterone receptor membrane component 1 (Pgrmc1) is related to cytochrome b 5 , binds to heme, and is associated with DNA damage resistance and apoptotic suppression. Pgrmc1 is induced by carcinogens, including dioxin, and is up-regulated in multiple types of cancer. In the present study, we found that Pgrmc1 increased in vivo tumor growth, anchorage-independent growth, and migration. Pgrmc1 also promoted proliferation in the absence of serum in A549 non-small cell lung cancer cells but enhanced proliferation regardless of serum concentration in MDA-MB-468 breast cancer cells. Pgrmc1 promotes cholesterol synthesis and binds to Insig (insulininduced gene), Scap (sterol regulatory element binding protein cleavage activating protein), and P450 proteins, but Pgrmc1 did not affect cholesterol synthesis in lung cancer cells. Pgrmc1 is also associated with progesterone signaling and plasminogen activator inhibitor (PAI1) RNA binding protein, but neither progesterone activity nor PAI1 transcript levels were altered in Pgrmc1-knockdown lung cancer cells. Pgrmc1 homologues bind to aryl ligands identified in an in silico screen, and we have found that a Pgrmc1 ligand induced cell death in a Pgrmc1-specific manner in multiple breast and lung tumor cell lines. Our data support a role for Pgrmc1 in promoting cancer-associated phenotypes and provide a therapeutic approach for targeting Pgrmc1 with a small molecule in lung and breast cancer.

Tumorigenesis requires the concerted action of multiple pathways, including pathways that stimulate proliferation and metabolism. Epidermal growth factor receptor (EGFR) is a transmembrane receptor-tyrosine kinase that is associated with cancer progression, and the EGFR inhibitors erlotinib/tarceva and tyrphostin/AG-1478 are potent anti-cancer therapeutics. Pgrmc1 (progesterone receptor membrane component 1) is a cytochrome b 5 -related protein that is up-regulated in tumors and promotes cancer growth. Pgrmc1 and its homologues have been implicated in cell signaling, and we show here that Pgrmc1 increases susceptibility to AG-1478 and erlotinib, increases plasma membrane EGFR levels, and co-precipitates with EGFR. Pgrmc1 co-localizes with EGFR in cytoplasmic vesicles and cofractionates with EGFR in high density microsomes. The findings have therapeutic potential because a Pgrmc1 small molecule ligand, which inhibits growth in a variety of cancer cell types, de-stabilized EGFR in multiple tumor cell lines. EGFR is one of the most potent receptor-tyrosine kinases driving tumorigenesis, and our data support a role for Pgrmc1 in promoting several cancer phenotypes at least in part by binding EGFR and stabilizing plasma membrane pools of the receptor.The proliferation of a number of cancers is driven by receptor-tyrosine kinases, which span the cell membrane and transmit signals from polypeptide hormones. Activation of the epidermal growth factor receptor (EGFR) 2 -tyrosine kinase has been linked to increased proliferation, angiogenesis, metastasis, and decreased apoptosis (1). EGFR is up-regulated in a variety of tumors (2), and EGFR and HER2/neu overexpression are associated with a poor prognosis in multiple tumor types (3). EGFR is inhibited by a growing number of drugs, including antibodies such as cetuximab and small molecule inhibitors such as erlotinib (Tarceva/OSI-774) and gefitinib (3, 4). However, the degree to which patients respond favorably to these drugs varies markedly between those expressing wild-type EGFR and mutants (5-7). One of the emerging themes in targeting kinases is the importance of processing events, intracellular transport, and interaction partners among the kinases (8,9). In the present study we demonstrate an association between EGFR and progesterone receptor membrane component 1 (Pgrmc1).Pgrmc1 is related to cytochrome b 5 and has binding sites for Src homology 2 (SH2) and SH3 domain-containing proteins and consensus phosphorylation sites for tyrosine kinases (10). Pgrmc1 is induced in a variety of cancers, including breast, thyroid, colon, ovary, and lung cancer (11-16). Furthermore, Pgrmc1 expression increases with tumor stage in ovarian cancer (11), and Pgrmc1 is elevated in estrogen receptor-negative breast tumors (17, 18). Pgrmc1 was originally identified by its induction by dioxin during liver tumorigenesis (19) and is one of six genes in a signature predicting non-genotoxic carcinogens (20). Pgrmc1 is required for key functions in tumor growth, promoting survival in cancer cells...