HSF1 is the key transcriptional regulator of heat shock protein synthesis that defines the response to hyperthermia, and affects resistance to certain conventional drugs and radiation. Recently, based on both model and population studies, Hsf1 has emerged as a major factor in breast cancer development. We have demonstrated that HSF1 plays an essential role in malignant transformation and maintenance of cancer cells by controlling oncogene-induced senescence, and tumor angiogenesis. To advance our understanding of oncogenesis and radiation resistance, and to rationally target Hsf1 in specific cancer types, here we will address fundamental questions: (1) what are the key mechanisms of Hsf1 activation in Her2-positive cancer, (2) how does Hsf1 affect development and progression of Her2-positive breast cancer, and (3) what is the role of HSF1 in resistance to ionizing radiation.
Aim 1 will address how HSF1 is regulated in mammary tumorigenesis. We will elucidate whether Hsf1 is constitutively activated in tumors because of aneuploidy-associated proteotoxicity by co-opting the signal transduction pathways observed in the heat shock response, or as a part of conventional HER2- mediated cancer signaling.
In Aim 2, we will clarify how Hsf1 enters functional complexes in response to Her2, and affects global transcription. We will then elucidate the role of transcription mediated by HSF1 in the cancer cells, establishing HSF1 as a cancer stem cell factor, a player in epithelial/mesenchymal transition and a determinant of tumor metastasis (Aim 3). Finally, we will establish how Hsf1 determines cancer responses to ionizing radiation by testing a hypothesis that radiation resistance is linked to Hsf1-mediated control of cancer stem cells.
Heat shock factor 1 is a protein recently shown to accumulate in breast cancer cells and is an indicator of the severity of the disease. In our proposed studies, we will ask how this protein is increased in an aggressive form of mammary cancer, with the purpose of understanding the etiology of the disease and enhancing its rational treatment with ionizing radiation.
|Meriin, Anatoli B; Narayanan, Arjun; Meng, Le et al. (2018) Hsp70-Bag3 complex is a hub for proteotoxicity-induced signaling that controls protein aggregation. Proc Natl Acad Sci U S A 115:E7043-E7052|
|Yaglom, Julia A; Wang, Yongmei; Li, Amy et al. (2018) Cancer cell responses to Hsp70 inhibitor JG-98: Comparison with Hsp90 inhibitors and finding synergistic drug combinations. Sci Rep 8:3010|
|McFarland, Christopher D; Yaglom, Julia A; Wojtkowiak, Jonathan W et al. (2017) The Damaging Effect of Passenger Mutations on Cancer Progression. Cancer Res 77:4763-4772|
|Gabai, Vladimir L; Yaglom, Julia A; Wang, Yongmei et al. (2016) Anticancer Effects of Targeting Hsp70 in Tumor Stromal Cells. Cancer Res 76:5926-5932|
|Calderwood, Stuart K; Gong, Jianlin (2016) Heat Shock Proteins Promote Cancer: It's a Protection Racket. Trends Biochem Sci 41:311-323|
|Calderwood, Stuart K (2016) A critical role for topoisomerase IIb and DNA double strand breaks in transcription. Transcription 7:75-83|
|Gong, J; Weng, D; Eguchi, T et al. (2015) Targeting the hsp70 gene delays mammary tumor initiation and inhibits tumor cell metastasis. Oncogene 34:5460-71|
|Bunch, Heeyoun; Lawney, Brian P; Lin, Yu-Fen et al. (2015) Transcriptional elongation requires DNA break-induced signalling. Nat Commun 6:10191|
|Sherman, M Y; Gabai, V L (2015) Hsp70 in cancer: back to the future. Oncogene 34:4153-61|
|Murshid, Ayesha; Gong, Jianlin; Prince, Thomas et al. (2015) Scavenger receptor SREC-I mediated entry of TLR4 into lipid microdomains and triggered inflammatory cytokine release in RAW 264.7 cells upon LPS activation. PLoS One 10:e0122529|
Showing the most recent 10 out of 14 publications