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 #
5R01CA062130-16
Application #
8067145
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
2011-05-01
Budget End
2012-04-30
Support Year
16
Fiscal Year
2011
Total Cost
$281,996
Indirect Cost
Name
Georgia Regents University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
966668691
City
Augusta
State
GA
Country
United States
Zip Code
30912
Jin, Xiongjie; Eroglu, Binnur; Moskophidis, Demetrius et al. (2018) Targeted Deletion of Hsf1, 2, and 4 Genes in Mice. Methods Mol Biol 1709:1-22
Jin, Xiongjie; Qiao, Aijun; Moskophidis, Demetrius et al. (2018) Modulation of Heat Shock Factor 1 Activity through Silencing of Ser303/Ser307 Phosphorylation Supports a Metabolic Program Leading to Age-Related Obesity and Insulin Resistance. Mol Cell Biol 38:
Habtetsion, Tsadik; Ding, Zhi-Chun; Pi, Wenhu et al. (2018) Alteration of Tumor Metabolism by CD4+ T Cells Leads to TNF-?-Dependent Intensification of Oxidative Stress and Tumor Cell Death. Cell Metab 28:228-242.e6
Zhang, Liyong; Wang, Yan; Rashid, Mohammad H et al. (2017) Malignant pericytes expressing GT198 give rise to tumor cells through angiogenesis. Oncotarget 8:51591-51607
Zhang, Liyong; Wang, Yan; Rashid, Mohammad H et al. (2017) Malignant pericytes expressing GT198 give rise to tumor cells through angiogenesis. Oncotarget :
Qiao, Aijun; Jin, Xiongjie; Pang, Junfeng et al. (2017) The transcriptional regulator of the chaperone response HSF1 controls hepatic bioenergetics and protein homeostasis. J Cell Biol 216:723-741
Sharma, Bal Krishan; Kolhe, Ravindra; Black, Stephen M et al. (2016) Inhibitor of differentiation 1 transcription factor promotes metabolic reprogramming in hepatocellular carcinoma cells. FASEB J 30:262-75
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
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

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