Researchers at the Cancer Science Institute of Singapore (CSI Singapore) at the National University of Singapore (NUS), in collaboration with Harvard Stem Cell Institute (HSCI), have discovered a new way in which the development of lung cancer can be stopped. In a study published in Science Translational Medicine, the researchers found that inhibiting a protein called BMI1 impaired tumour growth in lung cancer.
The study was led by HSCI Principal Faculty member Daniel Tenen, MD, his associate Elena Levantini, PhD, and included first author Dr Kol Jia Yong, a former CSI Singapore graduate student.
Lung cancer is one of the deadliest cancers in the world, accounting for 30% of tumour-related deaths1. Like many solid tumours, lung cancer is heterogeneous (consisting of cancer cells which behave and respond differently) and hence there is currently no single efficient drug which is able to treat all patients.
Teen, who is also the Director of CIS Singapore, has worked on the differentiation factor C/EBPα for several decades, demonstrating that it is an important tumor suppressor, first in acute myelogenous leukemia (AML), and subsequently, in studies in collaboration with Levantini, in lung cancer. In addition, loss of C/EBPα has also been found to have a role in the development of other cancer types such as hepatic, squamous cell, and prostate cancer 2-5. Despite this, the ways in which C/EBPα suppresses tumour formation still remains unknown.
In the past few years, Levantini continued the investigation C/EBPα in lung cancer. She confirmed that one subtype of lung cancer called non-small cell lung cancer (NSCLC) frequently expressed low levels of C/EBPα. Low or absent C/EBPα resulted in poorer survival when they corresponded with a reciprocally high expression of BMI1, a gene implicated in the development of tumors of colon, breast, and stomach, as well as some forms of leukemia. Levantini then went on to develop a mouse model in which deleting C/EBPα resulted in NSCLC. Analysis of this model led to the discovery that C/EBPα suppressed lung tumor formation by inhibiting the expression of BMI1. Levantini then demonstrated that reducing the levels of BMI1 in her mouse model by genetic means, or by using a drug reducing expression of BMI1, led to inhibition of tumor formation.
This study has established an important link between C/EBPα and BMI1 for the first time. Furthermore, these findings suggest that assessment of expression levels of these proteins could be used as a way to predict which patients might benefit from drugs which inhibit BMI1, some of which are currently being evaluated in clinical trials.
Moving forward, knowing the substantial role that BMI1 plays in the formation and development of aggressive lung cancer types, the findings of this study contributes the development of better therapies for cancer patients.
This work was funded by National Institutes of Health and National Cancer Institute (NIH/NCI P50 CA90578) Project 2 grant; the NCIS Yong Siew Yoon Research Grant through donations from the Yong Loo Lin Trust, the Singapore Ministry of Health's National Medical Research Council under its Singapore Translational Research (STaR) Investigator Award, and by the National Research Foundation of Singapore and the Singapore Ministry of Education under its Research Centres of Excellence initiative; FAMRI YCSA initiative; FAMRI YCSA 052409 and FAMRI CIA 103063, FAMRI YCSA 072165, Doctor's Cancer Foundation Award, IASLC Award, MIUR Flagship Interomics Project and MSMT Navrat grant LK21307. Researchers were supported by José Carreras fellowship, FIJC-10; NCI T32/K12/R25 award; the Agency for Science, Technology and Research (A*STAR), Singapore; the National Medical Research Council of Singapore (NMRC/CG/NCIS/2010) and the DF/HCC Cancer Center Support Grant 5P30 CA006516.
1 R. Siegel, D. Naishadham, A. Jemal, Cancer statistics, 2012. CA Cancer J. Clin. 62, 10–29 (2012).
2 E. H. Tan, S. C. Hooi, M. Laban, E. Wong, S. Ponniah, A. Wee, N.-d. Wang, CCAAT/enhancer binding protein α knock-in mice exhibit early liver glycogen storage and reduced susceptibility to hepatocellular carcinoma. Cancer Res. 65, 10330–10337 (2005).
3 H.-S. Oh, R. C. Smart, Expression of CCAAT/enhancer binding proteins (C/EBP) is associated with squamous differentiation in epidermis and isolated primary keratinocytes and is altered in skin neoplasms. J. Invest. Dermatol. 110, 939–945 (1998).
4 K. L. Bennett, B. Hackanson, L. T. Smith, C. D. Morrison, J. C. Lang, D. E. Schuller, F. Weber, C. Eng, C. Plass, Tumor suppressor activity of CCAAT/enhancer binding protein α is epigenetically down-regulated in head and neck squamous cell carcinoma. Cancer Res. 67, 4657–4664 (2007).
5 H. Yin, H. S. Radomska, D. G. Tenen, J. Glass, Down regulation of PSA by C/EBPα is ssociated with loss of AR expression and inhibition of PSA promoter activity in the LNCaP cell line. BMC Cancer 6, 158 (2006).