The challenge in breast cancer is not availability of treatment options, but that a significant number of women who receive treatment suffer a relapse and their cancer recurs. In addition, overtreatment of women who do not derive any clinical benefit from existing therapies exposes them to undesirable side effects and a compromised quality of life. Therefore, better stratification of patients is required to ensure personalized and effective strategies for their treatment. Our laboratory pursues both basic and application oriented approaches to resolve these issues. We work closely with an interdisciplinary network of clinicians, statisticians and computational biology experts to discover novel therapeutic targets using genomic and epigenomic tools and to design diagnostic/prognostic tests for women suffering from breast cancer.
Jumanji Domain containing protein 6 (JMJD6) and cancer
We discovered JMJD6 in a genotype to phenotype screen using meta-analysis of microarray data from over 2000s patient samples. We showed that high expression of this bifunctional histone arginine demethylase and lysyl hydroxylase associates with poor survival of women with breast cancer (3). More recently, we have mapped the gene regulation network and cancer specific pathways elucidated by JMJD6. We discovered that JMJD6 was crucial for the induction of a long-intervening non-coding RNA (HOTAIR) via a 21 bp sequence in its proximal promoter (1). HOTAIR has long been known to promote metastasis and death in breast cancer patients. Currently, we are initiating projects that study JMJD6 interacting proteins related to DNA replication and chemoresistance.
Development of Point-of-Care tests
1. Locally advanced breast cancer (LABC)
Multiple tests that predict the risk of breast cancer recurrence are available for ER+ and to some extent ER- early stage cancers. However, most women in India present with locally advanced disease at diagnosis. We have used in silico analysis to identify genes that correlate with poor prognosis in breast cancer when highly expressed. We have studied the biology of these genes to identify pathways they incite for avoiding cell death, increase cell proliferation and become refractory to treatment regimens. Combining these potentially prognostic genes with each other and downstream hallmark cancer pathways they invoke is powerful tool to improve their prognostic and predictive potential in cancer progression. We are currently studying a 17 gene signature to determine if they can serve both as a multigene prognostic as well as a predictive test in locally advanced breast cancers. We collaborate with Christian Medical College, Vellore in this project.
2. Liquid Biopsy based tests
Classic tissue biopsies often miss key markers for tumor classification and treatment due to biased sampling, tumor cell clonality and heterogeneity. Secondly, tumor samples from metastatic distal site tissues are also not represented. Blood-based liquid biopsies contain information from both the primary and metastatic tumors, are more adaptable to cheap screening tests and represent the future of cancer diagnosis/prognosis. Our basis for this test is isolating tumor-secreted vesicles (endocytic vesicles/exosomes) or circulating cell-free DNA (cfDNA) in blood and assaying their contents for cancer biomarkers. Such tests promote higher patient compliance since they are minimally invasive, and are clinically expedient for dynamic monitoring of patient’s response to treatment since they allow longitudinal sampling within the same patient. Our goal is to isolate tumor exosomes from the blood of breast cancer patients and to analyze their content for RNA/protein expression that will distinguish tumors by prognostic outcome and potential response to available treatments. This work is being carried out in collaboration with the University of Chicago and Tata Medical Center, Kolkata.
Biswas A, Shettar A, Mukherjee G, Kondaiah P, Desai KV. JMJD6 induces HOTAIR, an oncogenic lincRNA, by physically interacting with its proximal promoter. Biochem J. 2018 Jan 15;475(1):355-371
Biswas, A. and Desai, K.V. The LncRNA HOTAIR-expression, regulation and function in cancer Nucleus (2017) 60: 155
Lee YF, Miller LD, Chan XB, Black MA, Pang B, Ong CW, Salto-Tellez M, Liu ET, Desai KV*. JMJD6 is a driver of cellular proliferation and motility and a marker of poor prognosis in breast cancer. Breast Cancer Res. 2012 May 23;14(3):R85
4.Soon WW, Miller LD, Black MA, Dalmasso C, Chan XB, Pang B, Ong CW, Salto-Tellez M, Desai KV*, Liu ET. Combined genomic and phenotype screening reveals secretory factor SPINK1 as an invasion and survival factor associated with patient prognosis in breast cancer. EMBO Mol Med. 2011 Aug;3(8):451-64. (*corresponding author)
Fullwood MJ, Liu MH, Pan YF, Liu J, Xu H, Mohamed YB, Orlov YL, Velkov S, Ho A, Mei PH, Chew EG, Huang PY, Welboren WJ, Han Y, Ooi HS, Ariyaratne PN, Vega VB, Luo Y, Tan PY, Choy PY, Wansa KD, Zhao B, Lim KS, Leow SC, Yow JS, Joseph R, Li H, Desai KV, Thomsen JS, Lee YK, Karuturi RK, Herve T, Bourque G, Stunnenberg HG, Ruan X, Cacheux-Rataboul V, Sung WK, Liu ET, Wei CL, Cheung E, Ruan Y. An oestrogen-receptor-alpha-bound human chromatin interactome. Nature. 2009 Nov 5;462(7269):58-64