Loss of progesterone receptor links to high proliferation and increases from primary to metastatic endometrial cancer lesions

• Published in: European journal of cancer (1990) Vol. 50; no. 17; pp. 3003 - 3010
• Main Authors: Tangen, Ingvild Løberg, Werner, Henrica M.J, Berg, Anna, Halle, Mari K, Kusonmano, Kanthida, Trovik, Jone, Hoivik, Erling A, Mills, Gordon B, Krakstad, Camilla, Salvesen, Helga B
• Format: Journal Article
• Language: English
• Published: Kidlington Elsevier Ltd 01.11.2014; Elsevier
• Subjects: Adult; Aged; Antibiotics, Antineoplastic - therapeutic use; Biological and medical sciences; CDK inhibitors; Cell Proliferation - drug effects; Cell Proliferation - physiology; Chromones - therapeutic use; Disease Progression; Endometrial cancer; Endometrial Neoplasms - metabolism; Endometrial Neoplasms - mortality; Endometrial Neoplasms - pathology; Enzyme Inhibitors - therapeutic use; Female; Gene Expression Regulation, Neoplastic; Hematology, Oncology and Palliative Medicine; Humans; Medical sciences; Middle Aged; Morpholines - therapeutic use; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Oligonucleotide Array Sequence Analysis; Pharmacology. Drug treatments; Progesterone receptor; Prospective Studies; Protein Kinase Inhibitors - therapeutic use; Receptors, Progesterone - antagonists & inhibitors; Receptors, Progesterone - genetics; Receptors, Progesterone - metabolism; RNA, Messenger - metabolism; Sirolimus - therapeutic use; Survival; TOR Serine-Threonine Kinases - antagonists & inhibitors; Tumors; Endometrial cancer; Progesterone receptor; CDK inhibitors; Survival; Cell proliferation; Endometrium cancer; Increase; Malignant tumor; Metastasis; Female genital diseases; Cyclin dependent kinase inhibitor; Cancerology; Uterine diseases; Advanced stage; Lesion; Cancer; Hormonal receptor; Primary cancer
• ISSN: 0959-8049; 1879-0852
• DOI: 10.1016/j.ejca.2014.09.003

Abstract Objective In endometrial cancer loss of progesterone receptor (PR, gene name PGR ) is associated with aggressive disease and altered response to hormonal treatment. The aim of this study was to investigate changes in PR expression level with disease progression, and explore whether differences in gene expression according to PR status can be linked to processes involved in cancer development elucidating new therapeutic opportunities. Methods 686 primary endometrial cancers and 171 metastatic lesions were investigated for PR expression in relation to clinical and histopathological data. Protein levels were investigated by immunohistochemistry and reverse phase protein array, and mRNA levels by DNA oligonucleotide microarray. Results PR protein level was significantly associated with PGR mRNA expression ( P < 0.001) and patient survival ( P < 0.001). Loss of PR increased with disease progression, with 23% of the primary tumours and 76% of metastases demonstrating PR loss. Using a cell cycle progression signature score, PR loss was associated with increased proliferation for both oestrogen receptor (ER) positive and negative tumours. Through a Connectivity Map search, CDK inhibitors and other drugs with anti-proliferative effects were suggested in particular for treatment of patients with loss of PR. Conclusion Loss of PR in endometrial cancer is associated with increased proliferation, poor survival, and increases from primary to metastatic lesions. Based on expression profiles, CDK inhibitors may have activity in PR negative tumours, supporting further testing in clinical trials for patients with systemic endometrial cancer dependent on PR status.