PMID- 25659585
OWN - NLM
STAT- MEDLINE
DCOM- 20160128
LR  - 20200703
IS  - 1476-5594 (Electronic)
IS  - 0950-9232 (Print)
IS  - 0950-9232 (Linking)
VI  - 34
IP  - 43
DP  - 2015 Oct
TI  - Targeting the hsp70 gene delays mammary tumor initiation and inhibits tumor cell 
      metastasis.
PG  - 5460-71
LID - 10.1038/onc.2015.1 [doi]
AB  - Elevated levels of the inducible heat-shock protein 70 (Hsp72) have been 
      implicated in mammary tumorigenesis in histological investigations of human 
      breast cancer. We therefore examined the role of Hsp72 in mice, using animals in 
      which the hsp70 gene was inactivated. We used a spontaneous tumor system with 
      mice expressing the polyomavirus middle T (PyMT) oncogene under control of the 
      mouse mammary tumor virus (MMTV) long-terminal repeat (MMT mice). These mice 
      developed spontaneous, metastatic mammary cancer. We then showed Hsp72 to be 
      upregulated in a fraction of mammary cancer initiating cells (CIC) within the MMT 
      tumor cell population. These cells were characterized by elevated surface levels 
      of stem cell markers CD44 and Sca1 and by rapid metastasis. Inactivation of the 
      hsp70 gene delayed the initiation of mammary tumors. This delay in tumor 
      initiation imposed by loss of hsp70 was correlated with a decreased pool of CIC. 
      Interestingly, hsp70 knockout significantly reduced invasion and metastasis by 
      mammary tumor cells and implicated its product Hsp72 in cell migration and 
      formation of secondary neoplasms. Impaired tumorigenesis and metastasis in 
      hsp70-knockout MMT mice was associated with downregulation of the met gene and 
      reduced activition of the oncogenic c-Met protein. These experiments therefore 
      showed Hsp72 to be involved in the growth and progression of mammary carcinoma 
      and highlighted this protein as a potential target for anticancer drug 
      development.
FAU - Gong, J
AU  - Gong J
AD  - Department of Medicine, Boston University Medical Center, Boston, MA, USA.
FAU - Weng, D
AU  - Weng D
AD  - Department of Medicine, Boston University Medical Center, Boston, MA, USA.
FAU - Eguchi, T
AU  - Eguchi T
AD  - Molecular and Cellular Radiation Oncology, Beth Israel Deaconess Medical Center, 
      Harvard Medical School, Boston, MA, USA.
FAU - Murshid, A
AU  - Murshid A
AD  - Molecular and Cellular Radiation Oncology, Beth Israel Deaconess Medical Center, 
      Harvard Medical School, Boston, MA, USA.
FAU - Sherman, M Y
AU  - Sherman MY
AD  - Department of Biochemistry, Boston University Medical Center, Boston, MA, USA.
FAU - Song, B
AU  - Song B
AD  - Department of Medicine, Boston University Medical Center, Boston, MA, USA.
FAU - Calderwood, S K
AU  - Calderwood SK
AD  - Molecular and Cellular Radiation Oncology, Beth Israel Deaconess Medical Center, 
      Harvard Medical School, Boston, MA, USA.
LA  - eng
GR  - R01 CA047407/CA/NCI NIH HHS/United States
GR  - R01CA119045/CA/NCI NIH HHS/United States
GR  - R01 CA176326/CA/NCI NIH HHS/United States
GR  - R01CA47407/CA/NCI NIH HHS/United States
GR  - R01 CA119045/CA/NCI NIH HHS/United States
GR  - R01CA176326/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20150209
PL  - England
TA  - Oncogene
JT  - Oncogene
JID - 8711562
RN  - 0 (Antineoplastic Agents)
RN  - 0 (HSP72 Heat-Shock Proteins)
RN  - EC 2.7.10.1 (Proto-Oncogene Proteins c-met)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents/pharmacology
MH  - Cell Movement/drug effects/genetics
MH  - Cell Transformation, Neoplastic/drug effects/*genetics
MH  - Down-Regulation/drug effects/genetics
MH  - Female
MH  - HSP72 Heat-Shock Proteins/*genetics
MH  - Mammary Neoplasms, Experimental/genetics
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Neoplasm Metastasis/drug therapy/*genetics
MH  - Oncogenes/genetics
MH  - Proto-Oncogene Proteins c-met/genetics
PMC - PMC7331470
MID - NIHMS1600396
COIS- Conflict of interest All authors declare no conflict of interest.
EDAT- 2015/02/11 06:00
MHDA- 2016/01/29 06:00
PMCR- 2020/07/02
CRDT- 2015/02/10 06:00
PHST- 2014/01/22 00:00 [received]
PHST- 2014/11/24 00:00 [revised]
PHST- 2014/11/25 00:00 [accepted]
PHST- 2015/02/10 06:00 [entrez]
PHST- 2015/02/11 06:00 [pubmed]
PHST- 2016/01/29 06:00 [medline]
PHST- 2020/07/02 00:00 [pmc-release]
AID - onc20151 [pii]
AID - 10.1038/onc.2015.1 [doi]
PST - ppublish
SO  - Oncogene. 2015 Oct;34(43):5460-71. doi: 10.1038/onc.2015.1. Epub 2015 Feb 9.