A hallmark in the pathogenesis of cancer is the increased expression of heat shock proteins (Hsps) and other molecular chaperones. This has been observed in many human tumor types, and is considered to be an adaptive response to enhance tumor cell survival. Heat shock transcription factor 1 (Hsf1) is a major transactivator of Hsps and other molecular chaperones. Results from our laboratory and others indicate significant tumor inhibitory effect for specific tumor types in the absence of the hsf1 gene, suggesting it may be an excellent molecule for targeted therapy in the clinic. However, the extent to which hsf1 ablation can negatively impact a broad range of different tumor types need to be established. In addition, the mechanisms underlying the significant inhibition of tumorigenesis in the absence of the hsf1 gene, specifically for those tumor types that are impacted by inflammation, or are of epithelial origin that account for most malignancies remain largely unknown and needs further investigation. Mutant mice deficient in Hsf1 generated in our laboratory by conventional or conditional gene targeting strategies as well as a knock-in mouse line carrying Hsf1 with the S303A/S307A phosphorylation mutation (hsf14P), which predictably leads to a more transcriptionally active form of Hsf1, offer unique opportunities to address these important issues in the cancer biology at the whole organism level. During the next project period we plan to determine the impact of Hsf1 deletion in two tumor model systems: (1) a chemically induced hepatocellular carcinoma (HCC) that is a well-established model for chronic inflammation-induced cancer, and (2) a model of spontaneous mammary tumorigenesis that expresses Her2/Neu directed to the mammary gland epithelium.
In Aim 1, we will test the hypothesis that ablation of Hsf1, negatively impact cell transformation and HCC tumor progression largely based on the property to regulate components of inflammatory response in the tumor environment. We will: (1) determine the intrinsic and extrinsic factors involved in diethylnitrosamine-induced HCC when Hsf1 is deleted from the whole organism, or when it is deleted from specific cell types (e.g., hepatocytes or macrophages), and (2) examine HCC development under conditions where Hsf1 is constitutively active due to mutations in phosphorylation sites (hsf14P mice).
In Aim 2, we will test the hypothesis that hsf1 deficiency leads to reduction in mammary tumorigenesis induced by overexpression of Her2/Neu and this occurs through modification of the balance between prosurvival signaling induced by overexpression of Her2/Neu and anti- proliferative signaling induced by TGF2. We will (1) determine the role of Hsf1 in development of mammary tumors using transgenic mouse model expressing Her2/Neu proto-oncogene in mammary epithelium crossed with hsf1-deficient mice, and (2) determine the impact of hsf1 deficiency on mammary tumorigenesis when hsf1 is specifically deleted from epithelial cells before, or after, the initiation of tumorigenesis. We will use a conditional gene knockout technology to examine the effects of hsf1 deficiency in the Her2/Neu-induced breast cancer model for tumors of epithelial origin.

Public Health Relevance

Heat shock transcription factor 1 (Hsf1) is a major transactivator of heat shock proteins (Hsps) and other molecular chaperones that are often overexpressed in human tumors leading to development of cellular resistance to various treatment modalities. We have generated mouse models deficient in Hsf1 and have tested their response in two cancer models;(1) A chemically-induced hepatocellular carcinoma (HCC), and (2) a spontaneous mammary tumorigenesis model that expresses Her2/Neu directed to the mammary gland epithelium. We have found that Hsf1 deficient mice exhibit significant reduction in both tumorigenesis models. In proposed studies, we will examine the underlying mechanisms involved in this tumor inhibitory effect when Hsf1 is deleted from tumors using the above mouse models in anticipation of generation of novel therapeutics to inhibit this protein in human tumors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA062130-18
Application #
8460101
Study Section
Special Emphasis Panel (ZRG1-ONC-A (03))
Program Officer
Wong, Rosemary S
Project Start
1996-07-01
Project End
2014-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
18
Fiscal Year
2013
Total Cost
$265,076
Indirect Cost
$84,752
Name
Georgia Regents University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
966668691
City
Augusta
State
GA
Country
United States
Zip Code
30912
Yang, Zheqiong; Peng, Min; Cheng, Liang et al. (2016) GT198 Expression Defines Mutant Tumor Stroma in Human Breast Cancer. Am J Pathol 186:1340-50
Eroglu, Binnur; Min, Jin-Na; Zhang, Yan et al. (2014) An essential role for heat shock transcription factor binding protein 1 (HSBP1) during early embryonic development. Dev Biol 386:448-60
Hong, Yuan; Peng, Yibing; Guo, Z Sheng et al. (2014) Epitope-optimized alpha-fetoprotein genetic vaccines prevent carcinogen-induced murine autochthonous hepatocellular carcinoma. Hepatology 59:1448-58
Eroglu, Binnur; Kimbler, Donald E; Pang, Junfeng et al. (2014) Therapeutic inducers of the HSP70/HSP110 protect mice against traumatic brain injury. J Neurochem 130:626-41
Peng, Min; Zhang, Hao; Jaafar, Lahcen et al. (2013) Human ovarian cancer stroma contains luteinized theca cells harboring tumor suppressor gene GT198 mutations. J Biol Chem 288:33387-97
Bradley, Eric; Bieberich, Erhard; Mivechi, Nahid F et al. (2012) Regulation of embryonic stem cell pluripotency by heat shock protein 90. Stem Cells 30:1624-33
Xi, Caixia; Hu, Yanzhong; Buckhaults, Phillip et al. (2012) Heat shock factor Hsf1 cooperates with ErbB2 (Her2/Neu) protein to promote mammary tumorigenesis and metastasis. J Biol Chem 287:35646-57
Jin, Xiongjie; Eroglu, Binnur; Cho, Wonkyoung et al. (2012) Inactivation of heat shock factor Hsf4 induces cellular senescence and suppresses tumorigenesis in vivo. Mol Cancer Res 10:523-34
Wu, Juan; Li, Jiaqi; Salcedo, Rosalba et al. (2012) The proinflammatory myeloid cell receptor TREM-1 controls Kupffer cell activation and development of hepatocellular carcinoma. Cancer Res 72:3977-86
Antonov, Alexander S; Antonova, Galina N; Munn, David H et al. (2011) ýýVýý3 integrin regulates macrophage inflammatory responses via PI3 kinase/Akt-dependent NF-ýýB activation. J Cell Physiol 226:469-76

Showing the most recent 10 out of 38 publications