PMID- 31209687
OWN - NLM
STAT- MEDLINE
DCOM- 20200109
LR  - 20211204
IS  - 1573-7217 (Electronic)
IS  - 0167-6806 (Linking)
VI  - 177
IP  - 2
DP  - 2019 Sep
TI  - Somatic loss of PIK3R1 may sensitize breast cancer to inhibitors of the MAPK 
      pathway.
PG  - 325-333
LID - 10.1007/s10549-019-05320-x [doi]
AB  - PURPOSE: The PI3K pathway, which includes the PI3K catalytic subunits p110alpha 
      (PIK3CA) and the PI3K regulatory subunit p85alpha (PIK3R1), is the most frequently 
      altered pathway in cancer. We encountered a breast cancer patient whose tumor 
      contained a somatic alteration in PIK3R1. Some commercial sequencing platforms 
      suggest that somatic mutations in PIK3R1 may sensitize cancers to drugs that 
      inhibit the mammalian target of rapamycin (mTOR). However, a review of the 
      preclinical and clinical literature did not find evidence substantiating that 
      hypothesis. The purpose of this study was to knock out PIK3R1 in order to 
      determine the optimal therapeutic approach for breast cancers lacking p85alpha. 
      METHODS: We created an isogenic cellular system by knocking out both alleles of 
      the PIK3R1 gene in the non-tumorigenic human breast cell line MCF-10A. Knockout 
      cells were compared with wild-type cells by measuring growth, cellular signaling, 
      and response to drugs. RESULTS: We observed hyperphosphorylation of MEK in these 
      knockouts, which sensitized PIK3R1-null cells to a MEK inhibitor, trametinib. 
      However, they were not sensitized to the mTOR inhibitor, everolimus. CONCLUSIONS: 
      Our findings suggest that breast cancers with loss of p85alpha may not respond to 
      mTOR inhibition, but may be sensitive to MEK inhibition.
FAU - Turturro, Sanja B
AU  - Turturro SB
AD  - Division of Hematology, Oncology, and Cell Therapy, Department of Internal 
      Medicine, Rush University Medical Center, 1725 W. Harrison St., Chicago, IL, 
      60612, USA.
FAU - Najor, Matthew S
AU  - Najor MS
AD  - Division of Hematology, Oncology, and Cell Therapy, Department of Internal 
      Medicine, Rush University Medical Center, 1725 W. Harrison St., Chicago, IL, 
      60612, USA.
FAU - Yung, Timothy
AU  - Yung T
AD  - Division of Hematology, Oncology, and Cell Therapy, Department of Internal 
      Medicine, Rush University Medical Center, 1725 W. Harrison St., Chicago, IL, 
      60612, USA.
FAU - Portt, Liam
AU  - Portt L
AD  - Division of Hematology, Oncology, and Cell Therapy, Department of Internal 
      Medicine, Rush University Medical Center, 1725 W. Harrison St., Chicago, IL, 
      60612, USA.
FAU - Malarkey, Christopher S
AU  - Malarkey CS
AD  - School of Pharmacy, Rueckert-Hartman College for Health Professions, Regis 
      University, 3333 Regis Boulevard, H-28, Denver, CO, 80221-1099, USA.
FAU - Abukhdeir, Abde M
AU  - Abukhdeir AM
AUID- ORCID: 0000-0003-1172-5819
AD  - Division of Hematology, Oncology, and Cell Therapy, Department of Internal 
      Medicine, Rush University Medical Center, 1725 W. Harrison St., Chicago, IL, 
      60612, USA. abde_abukhdeir@rush.edu.
FAU - Cobleigh, Melody A
AU  - Cobleigh MA
AD  - Division of Hematology, Oncology, and Cell Therapy, Department of Internal 
      Medicine, Rush University Medical Center, 1725 W. Harrison St., Chicago, IL, 
      60612, USA.
LA  - eng
PT  - Journal Article
DEP - 20190617
PL  - Netherlands
TA  - Breast Cancer Res Treat
JT  - Breast cancer research and treatment
JID - 8111104
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Biomarkers, Tumor)
RN  - 0 (Protein Kinase Inhibitors)
RN  - EC 2.7.1.- (PIK3R1 protein, human)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.1.137 (Class Ia Phosphatidylinositol 3-Kinase)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents/pharmacology
MH  - Biomarkers, Tumor
MH  - Breast Neoplasms/*diagnosis/*genetics
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Class Ia Phosphatidylinositol 3-Kinase/*genetics/metabolism
MH  - Disease Models, Animal
MH  - Drug Resistance, Neoplasm/*genetics
MH  - Female
MH  - Gene Knockdown Techniques
MH  - Gene Targeting
MH  - Humans
MH  - *MAP Kinase Signaling System
MH  - Middle Aged
MH  - Neoplasm Metastasis
MH  - Neoplasm Staging
MH  - Protein Kinase Inhibitors/*pharmacology
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Signal Transduction/drug effects
MH  - TOR Serine-Threonine Kinases/metabolism
OTO - NOTNLM
OT  - BREAST CANCER
OT  - Cellular signaling
OT  - MEK
OT  - PIK3R1
OT  - Trametinib
EDAT- 2019/06/19 06:00
MHDA- 2020/01/10 06:00
CRDT- 2019/06/19 06:00
PHST- 2019/05/31 00:00 [received]
PHST- 2019/06/10 00:00 [accepted]
PHST- 2019/06/19 06:00 [pubmed]
PHST- 2020/01/10 06:00 [medline]
PHST- 2019/06/19 06:00 [entrez]
AID - 10.1007/s10549-019-05320-x [pii]
AID - 10.1007/s10549-019-05320-x [doi]
PST - ppublish
SO  - Breast Cancer Res Treat. 2019 Sep;177(2):325-333. doi: 
      10.1007/s10549-019-05320-x. Epub 2019 Jun 17.