DNA strand and Cancer Cell Oncology Research Concept.

Arming the Immune System to Fight Breast Cancer

Eliminating Cancer Cells

Our research focuses on strengthening the immune system to fight breast cancer, which is the second leading cause of cancer-related deaths among American women.

Abstract

The Northeast Texas region, including Hunt County, is a hot spot for breast cancer incidence, the second leading cause of cancer-related deaths among American women. The introduction of antiestrogen and anti-HER2 therapies has improved the clinical outcomes of breast cancer patients. However, in over half of these patients, cancer will recur and metastasize. A novel strategy is being pursued to restore the ability of the immune system to detect and eliminate cancer cells. Four critical genes that help cancer cells evade the immune system have been identified. Inhibition of these immune-evading genes is expected to be more efficient in eliminating cancer cells than therapies currently available.

Although each cell of a multicellular organism shares the same genetic information with every other cell, the emergence of new information is essential for successful organ development and maintenance throughout the life span of an organism. We will combine hypothesis and discovery-driven approaches to decipher the critical genetic and epigenetic events that coordinate the development and maintenance of organs and how these processes are deregulated in human diseases.

Mechanisms of Mammary Gland Development and Breast Cancer

Mechanisms that govern the maintenance of architecture and differentiated state of organs are deregulated in cancer. Mammary glands are one of the few organs that can undergo repeated cycles of remodeling and morphologic alterations. In each cycle, there are ample opportunities for the complex remodeling mechanisms of the mammary gland to go wrong and cause breast cancer, the second leading cause of cancer-related mortalities in American women. As the initial onset and progression of breast cancer are poorly understood, my laboratory’s long-term goal is to elucidate genetic and epigenetic mechanisms that modulate the plasticity of mammary gland architecture and functions. This may lead to better preventive and therapeutic strategies, a critical aspect of furthering the current success in breast cancer management.

Normal Mammary Acini in Organotypic Assays

The video on the left is of normal mammary acini in organotypic assays. The photo on the right is G1P3 induced Hyperplastic Acini.

G1P3 Induced Hyperplastic Acini

In breast cancer, the basic unit of mammary gland architecture, the acinus, becomes malignant and loses its structural integrity. Using organotypic assays (3D culture), we have discovered that G1P3, one of the first identified interferon (IFN) stimulated genes (ISGs), perturbs the architecture of normal acini by inhibiting the apoptosis of acinar luminal cells to cause hyperplasia. In breast cells, in addition to IFNs, the expression of G1P3 was also induced by estrogen. In agreement with these results, G1P3 was overexpressed in early and advanced stages of breast cancers. More importantly, elevated expression of G1P3 is significantly associated with poor outcomes in ER+ breast cancer, which highlights the clinical relevance of G1P3. Thus, we have uncovered a new arm of signaling used by immuno-endocrine pathways to disrupt cell and tissue architecture, which challenges the dogma of IFNs as the tumor suppressors of the innate immune network. This sparked a desire to understand the functions of G1P3 and other interferon-stimulated genes in modulating the relationship between tissue architecture and cellular functions in normal and diseased conditions. Our current efforts are focused on: 1) How does G1P3 modulate epithelial cell polarity and tissue organization? 2) Role of G1P3 in breast cancer development and progression, and 3) Role of G1P3 in modulating survival functions in immuno-endocrine signaling pathways.

Photo 1 is on the right and a normal mammary gland.

Normal Mammary Gland

Photo 2 is on the left and a G1P3 Overexpression in Early Stage Breast Cancer.

G1P3 Overexpression in Early Stage Breast Cancer

Featured Publications

Peer-Reviewed Publications

  • Cheriyath, V., Kuhns, M., Jacobs, B., Evangelista, P., Downs-Kelly, E., Tubbs, R., Crowe, J., and Borden, E.C. G1P3, an interferon- and estrogen-induced survival protein contributes to hyperplasia, tamoxifen resistance and poor outcomes in breast cancer. Oncogene. 2011. Epub 2011/10/15. doi: 10.1038/onc.2011.393. PubMed PMID: 21996729.
  • Cheriyath, V., Leaman, D.G. and Borden, E.C. Emerging Roles of FAM14 Family Members (ISG 6-16 and ISG 12) in Innate Immunity and Cancer. J. Interferon and. Cyto. Res., 2011, 31:173-81.
  • Cheriyath, V., Kuhns, M., Kalaycio, M.E. and Borden, E.C. Potentiation of apoptosis by histone deacetylase inhibitors and doxorubicin combination: cytoplasmic cathepsin B as a mediator of apoptosis in multiple myeloma. Br. J. Cancer, 2011, 104: 957-67.
  • Luszczek, W., Cheriyath, V., Borden, E.C., Mekhail, T. Combinations of DNA Methyltransferase and Histone Deacetylase Inhibitors Induce DNA Damage in Small Cell Lung Cancer Cells: Correlation of Resistance to Interferon Stimulated Gene Expression. Mol. Cancer Ther., 2010, 9:2309-21.
  • Bae, S., V. Cheriyath, B. Jacobs, F. Reu, and E. Borden. Reversal of methylation silencing of Apo2L/TRAIL receptor 1 (DR4) expression overcomes resistance of SK-MEL-3 and SK-MEL-28 melanoma cells to interferons (IFNs) or Apo2L/TRAIL. Oncogene, 2008, 27: 490 – 498.
  • Cheriyath, V., K. B. Glaser, J. F. Waring, R. Baz, M. A. Hussein, and E. C. Borden. G1P3, an IFN-induced survival factor, antagonizes TRAIL-induced apoptosis in human myeloma cells. J Clin Invest., 2007, 117: 3107-3117.
  • Cheriyath, V., Jacobs, B.S. and Hussein, M.A. Proteasome inhibitors in the Clinical Setting: Benefits and Strategies to Overcome Multiple Myeloma Resistance to Proteasome Inhibitors. Drugs R D., 2007, 8: 1-12.
  • Cheriyath, V. and Hussein, M.A. Osteopontin, angiogenesis and multiple myeloma. Leukemia, 2005, 19: 2203-5
  • Cheriyath, V., Desgranges, Z.P. and Roy, A.L. c-Src-dependent transcriptional activation of TFII-I, J. Biol. Chem., 2002, 277: 22798-22805.
  • Cheriyath, V., Balasubrahmanyam, A. and Kapoor, H.C. Purification and characterization of a 29 kDa poly(A)-binding protein from chickpea (Cicer arietinum) epicotyl, Indian J. Biochem. Biophys., 2001, 38: 258-262.
  • Cheriyath, V. and Roy, A.L. Structure-function analysis of TFII-I. Roles of the N-terminal end, basic region, and I-repeats, J. Biol. Chem., 2001, 276: 8377-8383.
  • Parker, R., Phan, T., Baumeister, P., Roy, B., Cheriyath, V., Roy, A.L. and Lee, A.S. Identification of TFII-I as the endoplasmic reticulum stress response element binding factor ERSF: its autoregulation by stress and interaction with ATF6, Mol. Cell Biol., 2001, 21: 3220-3233.
  • Cheriyath, V., Balasubrahmanyam, A. and Kapoor, H.C. Purification and characterization of a poly(A)-binding protein from chickpea (Cicer arietinum) epicotyl, Indian J. Biochem. Biophys., 2000, 37: 107-113.
  • Cheriyath, V. and Roy, A.L. Alternatively spliced isoforms of TFII-I. Complex formation, nuclear translocation, and differential gene regulation, J. Biol. Chem.,2000, 275: 26300-26308.
  • Novina, C.D., Kumar, S., Bajpai, U., Cheriyath, V., Zhang, K., Pillai, S., Wortis, H.H. and Roy, A.L. Regulation of nuclear localization and transcriptional activity of TFII-I by Bruton’s tyrosine kinase, Mol. Cell Biol., 1999, 19: 5014-5024.
  • Cheriyath, V., Novina, C.D. and Roy, A.L. TFII-I regulates Vbeta promoter activity through an initiator element, Mol. Cell Biol., 1998, 18: 4444-4454.
  • Kapoor, H.C., Venugopalan, C. and Sharma, N. Indian Journal of Experimental Biology., 1998, 36: 501-505.
  • Kim, D.W., Cheriyath, V., Roy, A.L. and Cochran, B.H. TFII-I enhances activation of the c-Fos promoter through interactions with upstream elements, Mol. Cell Biol., 1998, 18: 3310-3320.
  • Novina, C.D., Cheriyath, V. and Roy, A.L. Regulation of TFII-I activity by phosphorylation, J. Biol. Chem., 1998, 273: 33443-33448.
  • Grueneberg, D.A., Henry, R.W., Brauer, A., Novina, C.D., Cheriyath, V., Roy, A.L. and Gilman, M. A multifunctional DNA-binding protein that promotes the formation of serum response factor/homeodomain complexes: identity to TFII-I, Genes Dev., 1997, 11: 2482-2493.
  • Novina, C.D., Cheriyath, V., Denis, M.C. and Roy, A.L. Methods for studying the biochemical properties of an Inr element binding protein: TFII-I, Methods, 1997, 12: 254-263.
  • Venugopalan, C. and Kapoor, H.C. Single step isolation of plant RNA, Phytochemistry, 1997, 46: 1303-1305.
  • Venugopalan, C. and Srivastava, K.N. Ind. J. Food Science & Tech, 1996, 33: 389-392.

Abstracts

  • Jankowska, A.M., Szpurka, H., Cheriyath, V., Ng, K., Hu, Z., McDevitt, M., Saunthararajah, Y. and Maciejewski, J.P. Consequences of UTX Dysfunction in Myelodysplastic Syndrome (American Society of Hematology). 2011
  • Makishima, H., Khan, S., Jankowska, A., Sugimoto, Y., Zhenbo Hu, Z., Cheriyath, V., Mahfouz, R., Ebrahem, Q., Vatolin, S. and Saunthararajah. Y., et al. EZH2 Is Either Mutated or Downregulated in Patients with Loss of Heterozygosity of Chromosome 7/7q and Leads to Epigenetic Dysregulation Via Histone H3K27. (American Society of Hematology). 2011
  • Kuhns, M., Kalaycio, M., Reu, F., Maciejewski, J. and Cheriyath, V. GSK-3β Inhibitors in Over-coming Chemoresistance in Multiple Myeloma. ASH Annual Meeting. 2010.
  • Cheriyath, V., Kuhns, M., Kalaycio, M and Borden, E.C. Inflammatory signaling genes as predictive markers of vorinostat sensitivity in multiple myeloma. AACR Annual Meeting, 2010.
  • Luszczek, W., Cheriyath, V., Mekhail, T., Borden, E.C. 5-AZA-dC and HDAC Inhibitor Combination Induced DNA Damage in Small Cell Lung Cancer Cells: Correlation of Resistance to Interferon Stimulated Gene Expression. AACR Annual Meeting-2010.
  • Cheriyath, V., Luszczek, W., Jacobs, B.S. and Borden, E.C. Interferon (IFN)-stimulated genes (ISGs) as a resistance mechanism in cancer cell death. Tri-Society Annual Conference: Cellular and Cytokine Interactions in Health and Disease -2009.
  • Cheriyath, V., Jacobs, B.S., Kuhns, M., Evangelista, P.J., Budd, T.G., Crowe, J.P., Tubbs, R.R., and Borden, E.C. Molecular Role of the Antiapoptotic Protein G1P3 in Cytokine and Endo-crine Mediated Survival Signaling in Breast Cancer Cells. AACR Annual Meeting -2009.
  • Luszczek, W., Cheriyath, V., Mekhail, T., Borden, E.C. Synergistic interaction of 5-aza-deoxycytidine (5-AZA-dC) and histone deacetylase (HDAC) inhibitor MGCD0103 in small cell lung cancer (SCLC) cells. AACR Annual Meeting-2009.
  • Mahindra, A., Jacobs, B.S., Kalaycio., M., Borden, E.C. and Cheriyath, V. Epigenetic modulators in combination with doxorubicin in multiple myeloma – 2009
  • Cheriyath, V., Thomas, DG, Baz, R., Kalaycio, M and Borden EC. HDAC inhibitor plus doxorubicin combinations reverse apoptosis resistance in myeloma cells by triggering cathepsin mediated BAX activation, ASH Annual Meeting, 2008.
  • Cheriyath, V., Thomas, DG, Glaser, KB, Greenberg, CH et.al., Epigenetic regulation of IFN- α2b activity in multiple myeloma by a non-hydroxamate HDAC inhibitor A-423378. AACR Annual Meeting -2008.
  • Luszczek, W., Cheriyath, V., Mekhail, T., Borden, E.C., Effects of 5-aza-deoxycytidine (5-AZA-dC) and histone deacetylase (HDAC) inhibitors on proliferation and gene expression in small cell lung cancer cells. AACR Annual Meeting -2008.
  • Cheriyath, V., Glaser, K.B., Greenberg, C.H., Kalaycio, M. and Borden, E.C. Epigenetic Regulation of IFN- α2b in Multiple Myeloma by a Hydroxamic Acid Histone Deacetylase (HDAC) Inhibitor (SAHA) and a non-Hydroxamic Acid HDAC Inhibitor (A-423378). 43rd ASCO Annual Meeting, June 1-5, 2007.
  • Cheriyath, V., Hussein, M.A., Glaser, K.B., Greenberg, C.H. and Borden, E.C. G1P3 (ISG6-16), an Interferon (IFN) stimulated survival factor antagonizes Apo2L/TRAIL induced apoptosis in myeloma cells. AACR Centennial Meeting, April 14-18, 2007.
  • Cheriyath, V., Hussein, M.A. and Borden, E.C. G1P3 an Interferon Stimulated Gene (ISG) antagonizes TRAIL induced apoptosis in Myeloma. Cytokine 2006,ISICR, meeting, Vienna, 2006.
  • Cheriyath, V., Hussein, M.A. and Borden, E.C. Epigenetically Regulated Interferons Activity in Multiple Myeloma by Histone Deacetylase Inhibitors, 97th AACR Annual Meeting, April 1-5, 2006.
  • Cheriyath, V., Nguyen, H., MacLeod, R., Hussein, M.A. and Borden, E.C. Epigenetically Regulated Interferons Activity in Multiple Myeloma by Isotype-Selective HDAC inhibitor MGCD0103. Clin. Cancer Res. 11 [24 Suppl], 9006s. 12-15, 2005.
  • Cheriyath, V., Hussein, M.A. and Borden, E.C. Epigenetically Regulated Interferon (IFN) Stimulated Genes: Potential Role in Augmenting the Antigrowth Activity of IFNs in Multiple Myeloma, 96th AACR Annual Meeting, 2005.
  • Cheriyath, V., Hussein, M.A. and Borden, E.C. Epigenetic Regulators: Potential Role in Augmenting IFNs antitumor Effects in Multiple Myeloma., Think Tank on Molecular Targets in Lymphoid Malignancies, 2005.
  • Cheriyath, V., Nguyen, H., Macleod, R.A., Hussein, M.A. and Borden, E.C. Epigenetic Regulation of IFN Activity in Multiple Myeloma by the Isotype-Selective HDAC Inhibitor MGCD0103., AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics: Discovery, Biology, and Clinical Applications, Philadelphia, 2005.
  • Masci, P., Cheriyath, V., Wood, L., Rybicki, L., Jacobs, B., Williams, B.R., Faber, P., Burkowski, R., Tong, K. and Borden, E.C. Clinical and Biological Evaluation of IFN alpha-1b: Gene Modulation and Clinical Effects, International Society for Interferon and Cytokine Research, 2005.
  • Cheriyath, V. and Roy, A.L. Role of Src in Internalization and Nuclear Sorting of the Transcription factor TFII-I, Cold Spring Harbor Laboratory-Tyrosine Phosphorylation and Cell Signaling, 2001.
  • Cheriyath, V. and Roy, A.L. Role of Src in Activation and Nuclear translocation of the Transcription factor TFII-I, Keystone Symposia – The Molecular Basis of Cancer: Signaling to Cell Growth and Death, 2001.
  • Gruenberg, D.A., Henry, R.W., Brauer, A., Novina, C.D., Cheriyath, V. and Roy, A.L. A Multifunctional DNA-Binding Protein that Promotes the Formation of Serum Response Factor/Homeodomain Complexes, Identity to TFII-I, Cold Spring Harbor Laboratory-Mechanisms of Eukaryotic Transcription, 1997.
  • Kim, D.W., Cheriyath, V., Roy, A.L. and Cochran, B.H. TFII-I Enhances Activation of the c-Fos Promoter and Forms a Complex with SRF, Cold Spring Harbor Laboratory-Mechanisms of Eukaryotic Transcription, 1997.
  • Novina, C.D., Bajpai, U., Cheriyath, V., Wortis, H.H. and Roy, A.L. Processing of Induced Signals into Transcriptional Responses via TFII-I, Cold Spring Harbor Laboratory-Mechanisms of Eukaryotic Transcription, 1997.
  • Venugopalan, C. and Kapoor, H.C. 2nd International Crop Science Congress, 1996.
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