Author
Saraswati Sukumar
Other affiliations: Tufts University, Salk Institute for Biological Studies, Walter Reed Army Medical Center ...read more
Bio: Saraswati Sukumar is an academic researcher from Johns Hopkins University School of Medicine. The author has contributed to research in topics: Breast cancer & Cancer. The author has an hindex of 77, co-authored 248 publications receiving 26027 citations. Previous affiliations of Saraswati Sukumar include Tufts University & Salk Institute for Biological Studies.
Topics: Breast cancer, Cancer, DNA methylation, Carcinogenesis, Metastasis
Papers published on a yearly basis
Papers
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TL;DR: It is shown that lincRNAs in the HOX loci become systematically dysregulated during breast cancer progression, indicating that l incRNAs have active roles in modulating the cancer epigenome and may be important targets for cancer diagnosis and therapy.
Abstract: Large intervening non-coding RNAs (lincRNAs) are pervasively transcribed in the genome yet their potential involvement in human disease is not well understood. Recent studies of dosage compensation, imprinting, and homeotic gene expression suggest that individual lincRNAs can function as the interface between DNA and specific chromatin remodelling activities. Here we show that lincRNAs in the HOX loci become systematically dysregulated during breast cancer progression. The lincRNA termed HOTAIR is increased in expression in primary breast tumours and metastases, and HOTAIR expression level in primary tumours is a powerful predictor of eventual metastasis and death. Enforced expression of HOTAIR in epithelial cancer cells induced genome-wide re-targeting of Polycomb repressive complex 2 (PRC2) to an occupancy pattern more resembling embryonic fibroblasts, leading to altered histone H3 lysine 27 methylation, gene expression, and increased cancer invasiveness and metastasis in a manner dependent on PRC2. Conversely, loss of HOTAIR can inhibit cancer invasiveness, particularly in cells that possess excessive PRC2 activity. These findings indicate that lincRNAs have active roles in modulating the cancer epigenome and may be important targets for cancer diagnosis and therapy.
4,605 citations
TL;DR: In this paper, gene expression and genetic profiles of cells purified from cancerous and normal breast tissue using markers previously associated with stem-cell-like properties were determined using markers from the TGF-β pathway, where its inhibition induced a more epithelial phenotype.
1,380 citations
TL;DR: In this article, an ultra-high-density array that tiles the promoters of 56 cell-cycle genes was used to interrogate 108 samples representing diverse perturbations, identifying 216 transcribed regions that encode putative lncRNAs, many with RT-PCR-validated periodic expression during the cell cycle.
Abstract: Transcription of long noncoding RNAs (lncRNAs) within gene regulatory elements can modulate gene activity in response to external stimuli, but the scope and functions of such activity are not known. Here we use an ultrahigh-density array that tiles the promoters of 56 cell-cycle genes to interrogate 108 samples representing diverse perturbations. We identify 216 transcribed regions that encode putative lncRNAs, many with RT-PCR-validated periodic expression during the cell cycle, show altered expression in human cancers and are regulated in expression by specific oncogenic stimuli, stem cell differentiation or DNA damage. DNA damage induces five lncRNAs from the CDKN1A promoter, and one such lncRNA, named PANDA, is induced in a p53-dependent manner. PANDA interacts with the transcription factor NF-YA to limit expression of pro-apoptotic genes; PANDA depletion markedly sensitized human fibroblasts to apoptosis by doxorubicin. These findings suggest potentially widespread roles for promoter lncRNAs in cell-growth control.
969 citations
01 Jun 2011
TL;DR: This work uses an ultrahigh-density array that tiles the promoters of 56 cell-cycle genes to interrogate 108 samples representing diverse perturbations and identifies 216 transcribed regions that encode putative lncRNAs, many with RT-PCR–validated periodic expression during the cell cycle.
Abstract: Transcription of long noncoding RNAs (lncRNAs) within gene regulatory elements can modulate gene activity in response to external stimuli, but the scope and functions of such activity are not known. Here we use an ultrahigh-density array that tiles the promoters of 56 cell-cycle genes to interrogate 108 samples representing diverse perturbations. We identify 216 transcribed regions that encode putative lncRNAs, many with RT-PCR-validated periodic expression during the cell cycle, show altered expression in human cancers and are regulated in expression by specific oncogenic stimuli, stem cell differentiation or DNA damage. DNA damage induces five lncRNAs from the CDKN1A promoter, and one such lncRNA, named PANDA, is induced in a p53-dependent manner. PANDA interacts with the transcription factor NF-YA to limit expression of pro-apoptotic genes; PANDA depletion markedly sensitized human fibroblasts to apoptosis by doxorubicin. These findings suggest potentially widespread roles for promoter lncRNAs in cell-growth control.
933 citations
TL;DR: Each of the Ha-ras-1 oncogenes present in tumours induced by N-nitroso-N-methylurea, but not in those induced by 7,12-dimethylbenz(a)anthracene, became activated by the same G → A transition, the type of mutation induced by W → N → G → M transition.
Abstract: Induction of mammary carcinomas in rats by a single exposure to a carcinogen during sexual development often involves malignant activation of the Ha-ras-1 locus. Each of the Ha-ras-1 oncogenes present in tumours induced by N-nitroso-N-methylurea, but not in those induced by 7,12-dimethylbenz(a)anthracene, became activated by the same G----A transition, the type of mutation induced by N-nitroso-N-methylurea. These results are consistent with the notion that Ha-ras-1 oncogenes are directly activated by the carcinogen during initiation of neoplasia.
807 citations
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TL;DR: It is reported that the induction of an EMT in immortalized human mammary epithelial cells (HMLEs) results in the acquisition of mesenchymal traits and in the expression of stem-cell markers, and it is shown that those cells have an increased ability to form mammospheres, a property associated with mammARY epithelial stem cells.
8,052 citations
TL;DR: The reprogramming of gene expression during EMT, as well as non-transcriptional changes, are initiated and controlled by signalling pathways that respond to extracellular cues, and the convergence of signalling pathways is essential for EMT.
Abstract: The transdifferentiation of epithelial cells into motile mesenchymal cells, a process known as epithelial-mesenchymal transition (EMT), is integral in development, wound healing and stem cell behaviour, and contributes pathologically to fibrosis and cancer progression. This switch in cell differentiation and behaviour is mediated by key transcription factors, including SNAIL, zinc-finger E-box-binding (ZEB) and basic helix-loop-helix transcription factors, the functions of which are finely regulated at the transcriptional, translational and post-translational levels. The reprogramming of gene expression during EMT, as well as non-transcriptional changes, are initiated and controlled by signalling pathways that respond to extracellular cues. Among these, transforming growth factor-β (TGFβ) family signalling has a predominant role; however, the convergence of signalling pathways is essential for EMT.
6,036 citations
TL;DR: The paradoxical roles of the tumor microenvironment during specific stages of cancer progression and metastasis are discussed, as well as recent therapeutic attempts to re-educate stromal cells within the TME to have anti-tumorigenic effects.
Abstract: Cancers develop in complex tissue environments, which they depend on for sustained growth, invasion and metastasis. Unlike tumor cells, stromal cell types within the tumor microenvironment (TME) are genetically stable and thus represent an attractive therapeutic target with reduced risk of resistance and tumor recurrence. However, specifically disrupting the pro-tumorigenic TME is a challenging undertaking, as the TME has diverse capacities to induce both beneficial and adverse consequences for tumorigenesis. Furthermore, many studies have shown that the microenvironment is capable of normalizing tumor cells, suggesting that re-education of stromal cells, rather than targeted ablation per se, may be an effective strategy for treating cancer. Here we discuss the paradoxical roles of the TME during specific stages of cancer progression and metastasis, as well as recent therapeutic attempts to re-educate stromal cells within the TME to have anti-tumorigenic effects.
5,396 citations
Journal Article•
TL;DR: It appeared that ras gene mutations can be found in a variety of tumor types, although the incidence varies greatly and some evidence that environmental agents may be involved in the induction of the mutations.
Abstract: Mutations in codon 12, 13, or 61 of one of the three ras genes, H-ras, K-ras, and N-ras, convert these genes into active oncogenes. Rapid assays for the detection of these point mutations have been developed recently and used to investigate the role mutated ras genes play in the pathogenesis of human tumors. It appeared that ras gene mutations can be found in a variety of tumor types, although the incidence varies greatly. The highest incidences are found in adenocarcinomas of the pancreas (90%), the colon (50%), and the lung (30%); in thyroid tumors (50%); and in myeloid leukemia (30%). For some tumor types a relationship may exist between the presence of a ras mutation and clinical or histopathological features of the tumor. There is some evidence that environmental agents may be involved in the induction of the mutations.
5,367 citations
TL;DR: It is shown that lincRNAs in the HOX loci become systematically dysregulated during breast cancer progression, indicating that l incRNAs have active roles in modulating the cancer epigenome and may be important targets for cancer diagnosis and therapy.
Abstract: Large intervening non-coding RNAs (lincRNAs) are pervasively transcribed in the genome yet their potential involvement in human disease is not well understood. Recent studies of dosage compensation, imprinting, and homeotic gene expression suggest that individual lincRNAs can function as the interface between DNA and specific chromatin remodelling activities. Here we show that lincRNAs in the HOX loci become systematically dysregulated during breast cancer progression. The lincRNA termed HOTAIR is increased in expression in primary breast tumours and metastases, and HOTAIR expression level in primary tumours is a powerful predictor of eventual metastasis and death. Enforced expression of HOTAIR in epithelial cancer cells induced genome-wide re-targeting of Polycomb repressive complex 2 (PRC2) to an occupancy pattern more resembling embryonic fibroblasts, leading to altered histone H3 lysine 27 methylation, gene expression, and increased cancer invasiveness and metastasis in a manner dependent on PRC2. Conversely, loss of HOTAIR can inhibit cancer invasiveness, particularly in cells that possess excessive PRC2 activity. These findings indicate that lincRNAs have active roles in modulating the cancer epigenome and may be important targets for cancer diagnosis and therapy.
4,605 citations