PMID- 31428575
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20201001
IS  - 2234-943X (Print)
IS  - 2234-943X (Electronic)
IS  - 2234-943X (Linking)
VI  - 9
DP  - 2019
TI  - Glutamine Metabolism Drives Growth in Advanced Hormone Receptor Positive Breast 
      Cancer.
PG  - 686
LID - 10.3389/fonc.2019.00686 [doi]
LID - 686
AB  - Dependence on the glutamine pathway is increased in advanced breast cancer cell 
      models and tumors regardless of hormone receptor status or function. While 70% of 
      breast cancers are estrogen receptor positive (ER+) and depend on estrogen 
      signaling for growth, advanced ER+ breast cancers grow independent of estrogen. 
      Cellular changes in amino acids such as glutamine are sensed by the mammalian 
      target of rapamycin (mTOR) complex, mTORC1, which is often deregulated in ER+ 
      advanced breast cancer. Inhibitor of mTOR, such as everolimus, has shown modest 
      clinical activity in ER+ breast cancers when given with an antiestrogen. Here we 
      show that breast cancer cell models that are estrogen independent and 
      antiestrogen resistant are more dependent on glutamine for growth compared with 
      their sensitive parental cell lines. Co-treatment of CB-839, an inhibitor of GLS, 
      an enzyme that converts glutamine to glutamate, and everolimus interrupts the 
      growth of these endocrine resistant xenografts. Using human tumor microarrays, we 
      show that GLS is significantly higher in human breast cancer tumors with 
      increased tumor grade, stage, ER-negative and progesterone receptor (PR) negative 
      status. Moreover, GLS levels were significantly higher in breast tumors from 
      African-American women compared with Caucasian women regardless of ER or PR 
      status. Among patients treated with endocrine therapy, high GLS expression was 
      associated with decreased disease free survival (DFS) from a multivariable model 
      with GLS expression treated as dichotomous. Collectively, these findings suggest 
      a complex biology for glutamine metabolism in driving breast cancer growth. 
      Moreover, targeting GLS and mTOR in advanced breast cancer may be a novel 
      therapeutic approach in advanced ER+ breast cancer.
FAU - Demas, Diane M
AU  - Demas DM
AD  - Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown 
      University Medical Center, Washington, DC, United States.
FAU - Demo, Susan
AU  - Demo S
AD  - Calithera Biosciences, South San Francisco, CA, United States.
FAU - Fallah, Yassi
AU  - Fallah Y
AD  - Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown 
      University Medical Center, Washington, DC, United States.
FAU - Clarke, Robert
AU  - Clarke R
AD  - Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown 
      University Medical Center, Washington, DC, United States.
FAU - Nephew, Kenneth P
AU  - Nephew KP
AD  - Cell, Molecular and Cancer Biology, Medical Sciences, Indiana University School 
      of Medicine, Bloomington, IN, United States.
FAU - Althouse, Sandra
AU  - Althouse S
AD  - Department of Biostatistics, Indiana University School of Medicine, Indianapolis, 
      IN, United States.
FAU - Sandusky, George
AU  - Sandusky G
AD  - Department of Pathology and Laboratory Medicine, Indiana University School of 
      Medicine, Indianapolis, IN, United States.
FAU - He, Wei
AU  - He W
AD  - Program in Genetics, Bioinformatics, and Computational Biology, VT BIOTRANS, 
      Virginia Tech, Blacksburg, VA, United States.
FAU - Shajahan-Haq, Ayesha N
AU  - Shajahan-Haq AN
AD  - Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown 
      University Medical Center, Washington, DC, United States.
LA  - eng
GR  - P30 CA051008/CA/NCI NIH HHS/United States
GR  - R01 CA201092/CA/NCI NIH HHS/United States
PT  - Journal Article
DEP - 20190802
PL  - Switzerland
TA  - Front Oncol
JT  - Frontiers in oncology
JID - 101568867
PMC - PMC6688514
OTO - NOTNLM
OT  - CB-839
OT  - breast cancer
OT  - endocrine resistance
OT  - everolimus
OT  - glutamine metabolism
OT  - mTOR
EDAT- 2019/08/21 06:00
MHDA- 2019/08/21 06:01
PMCR- 2019/01/01
CRDT- 2019/08/21 06:00
PHST- 2019/05/10 00:00 [received]
PHST- 2019/07/12 00:00 [accepted]
PHST- 2019/08/21 06:00 [entrez]
PHST- 2019/08/21 06:00 [pubmed]
PHST- 2019/08/21 06:01 [medline]
PHST- 2019/01/01 00:00 [pmc-release]
AID - 10.3389/fonc.2019.00686 [doi]
PST - epublish
SO  - Front Oncol. 2019 Aug 2;9:686. doi: 10.3389/fonc.2019.00686. eCollection 2019.