PMID- 35441158
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20220424
IS  - 2692-3114 (Electronic)
IS  - 2692-3114 (Linking)
VI  - 3
IP  - 1
DP  - 2022 Feb 28
TI  - Collateral-resistance to estrogen and HER-activated growth is associated with 
      modified AKT, ERalpha, and cell-cycle signaling in a breast cancer model.
PG  - 97-116
LID - 10.37349/etat.2022.00074 [doi]
AB  - AIM: A model of progressively endocrine-resistant breast cancer was investigated 
      to identify changes that can occur in signaling pathways after endocrine 
      manipulation. METHODS: The MCF7 breast cancer model is sensitive to estrogens and 
      anti-estrogens while variant lines previously derived from wild-type MCF7 are 
      either relatively 17beta-estradiol (E(2))-insensitive (LCC1) or fully resistant to 
      estrogen and anti-estrogens (LCC9). RESULTS: In LCC1 and LCC9 cell lines, loss of 
      estrogen sensitivity was accompanied by loss of growth response to transforming 
      growth factor alpha (TGFalpha), heregulin-beta and pertuzumab. LCC1 and LCC9 cells 
      had enhanced AKT phosphorylation relative to MCF7 which was reflected in 
      downstream activation of phospho-mechanistic target of rapamycin (mTOR), 
      phospho-S6, and phospho-estrogen receptor alpha Ser167 [ERalpha(Ser167)]. Both AKT2 
      and AKT3 were phosphorylated in the resistant cell lines, but small interfering 
      RNA (siRNA) knockdown suggested that all three AKT isoforms contributed to growth 
      response. ERalpha(Ser118) phosphorylation was increased by E(2) and TGFalpha in MCF7, by 
      E(2) only in LCC1, but by neither in LCC9 cells. Multiple alterations in 
      E(2)-mediated cell cycle control were identified in the endocrine-resistant cell 
      lines including increased expression of MYC, cyclin A1, cyclin D1, 
      cyclin-dependent kinase 1 (CDK1), CDK2, and hyperphosphorylated retinoblastoma 
      protein (ppRb), whereas p21 and p27 were reduced. Estrogen modulated expression 
      of these regulators in MCF7 and LCC1 cells but not in LCC9 cells. Seliciclib 
      inhibited CDK2 activation in MCF7 cells but not in resistant variants; in all 
      lines, it reduced ppRb, increased p53 associated responses including p21, p53 
      up-regulated modulator of apoptosis (PUMA), and p53 apoptosis-inducing protein 1 
      (p53AIP1), inhibited growth, and produced G2/M block and apoptosis. CONCLUSIONS: 
      Multiple changes occur with progression of endocrine resistance in this model 
      with AKT activation contributing to E(2) insensitivity and loss of ERalpha(Ser118) 
      phosphorylation being associated with full resistance. Cell cycle regulation is 
      modified in endocrine-resistant breast cancer cells, and seliciclib is effective 
      in both endocrine-sensitive and resistant diseases.
FAU - Moore, Kate M
AU  - Moore KM
AUID- ORCID: 0000-0002-1205-5186
AD  - Cancer Research UK Edinburgh Centre, Institute of Genetics and Cancer, University 
      of Edinburgh, Crewe Road South, EH4 2XR Edinburgh, UK.
AD  - Cancer Research UK Barts Centre, Barts and The London School of Medicine and 
      Dentistry, Queen Mary University of London, Charterhouse Square, EC1M 6BQ London, 
      UK.
FAU - Cerqueira, Vera
AU  - Cerqueira V
AD  - Cancer Research UK Edinburgh Centre, Institute of Genetics and Cancer, University 
      of Edinburgh, Crewe Road South, EH4 2XR Edinburgh, UK.
AD  - West of Scotland Clinical Genetics Service, Queen Elizabeth University Hospital, 
      G51 4TF Glasgow, UK.
FAU - MacLeod, Kenneth G
AU  - MacLeod KG
AD  - Cancer Research UK Edinburgh Centre, Institute of Genetics and Cancer, University 
      of Edinburgh, Crewe Road South, EH4 2XR Edinburgh, UK.
FAU - Mullen, Peter
AU  - Mullen P
AD  - School of Medicine, University of St Andrews, North Haugh, KY16 9TF St Andrews, 
      UK.
FAU - Hayward, Richard L
AU  - Hayward RL
AD  - Cancer Research UK Edinburgh Centre, Institute of Genetics and Cancer, University 
      of Edinburgh, Crewe Road South, EH4 2XR Edinburgh, UK.
FAU - Green, Simon
AU  - Green S
AUID- ORCID: 0000-0001-5054-4792
AD  - Cyclacel Ltd, James Lindsay Place, Dundee Technopole, DD1 5JJ Dundee, UK.
FAU - Harrison, David J
AU  - Harrison DJ
AUID- ORCID: 0000-0001-9041-9988
AD  - School of Medicine, University of St Andrews, North Haugh, KY16 9TF St Andrews, 
      UK.
FAU - Cameron, David A
AU  - Cameron DA
AUID- ORCID: 0000-0002-2717-7979
AD  - Cancer Research UK Edinburgh Centre, Institute of Genetics and Cancer, University 
      of Edinburgh, Crewe Road South, EH4 2XR Edinburgh, UK.
FAU - Langdon, Simon P
AU  - Langdon SP
AUID- ORCID: 0000-0002-7200-9237
AD  - Cancer Research UK Edinburgh Centre, Institute of Genetics and Cancer, University 
      of Edinburgh, Crewe Road South, EH4 2XR Edinburgh, UK.
LA  - eng
GR  - A5010/CRUK_/Cancer Research UK/United Kingdom
GR  - A6769/CRUK_/Cancer Research UK/United Kingdom
PT  - Journal Article
PL  - United States
TA  - Explor Target Antitumor Ther
JT  - Exploration of targeted anti-tumor therapy
JID - 101770662
PMC - PMC7612628
MID - EMS143780
OTO - NOTNLM
OT  - Breast cancer
OT  - endocrine resistance
OT  - erbB receptor
OT  - estrogen
OT  - seliciclib
COIS- Conflicts of interest The authors declare that they have no conflicts of 
      interest.
EDAT- 2022/04/21 06:00
MHDA- 2022/04/21 06:01
PMCR- 2022/02/28
CRDT- 2022/04/20 05:56
PHST- 2022/04/20 05:56 [entrez]
PHST- 2022/04/21 06:00 [pubmed]
PHST- 2022/04/21 06:01 [medline]
PHST- 2022/02/28 00:00 [pmc-release]
AID - etat-03-100274 [pii]
AID - 10.37349/etat.2022.00074 [doi]
PST - ppublish
SO  - Explor Target Antitumor Ther. 2022 Feb 28;3(1):97-116. doi: 
      10.37349/etat.2022.00074.