PMID- 33809171
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20210408
IS  - 2072-6694 (Print)
IS  - 2072-6694 (Electronic)
IS  - 2072-6694 (Linking)
VI  - 13
IP  - 6
DP  - 2021 Mar 12
TI  - Autophagy Triggers Tamoxifen Resistance in Human Breast Cancer Cells by 
      Preventing Drug-Induced Lysosomal Damage.
LID - 10.3390/cancers13061252 [doi]
LID - 1252
AB  - Endocrine resistance is a major complication during treatment of estrogen 
      receptor-positive breast cancer. Although autophagy has recently gained 
      increasing consideration among the causative factors, the link between autophagy 
      and endocrine resistance remains elusive. Here, we investigate the 
      autophagy-based mechanisms of tamoxifen resistance in MCF7 cells. Tamoxifen (Tam) 
      triggers autophagy and affects the lysosomal compartment of MCF7 cells, such that 
      activated autophagy supports disposal of tamoxifen-damaged lysosomes by 
      lysophagy. MCF7 cells resistant to 5 microM tamoxifen (MCF7-TamR) have a higher 
      autophagic flux and an enhanced resistance to Tam-induced lysosomal alterations 
      compared to parental cells, which suggests a correlation between the two events. 
      MCF7-TamR cells overexpress messenger RNAs (mRNAs) for metallothionein 2A and 
      ferritin heavy chain, and they are re-sensitized to Tam by inhibition of 
      autophagy. Overexpressing these proteins in parental MCF7 cells protects 
      lysosomes from Tam-induced damage and preserves viability, while inhibiting 
      autophagy abrogates lysosome protection. Consistently, we also demonstrate that 
      other breast cancer cells that overexpress selected mRNAs encoding iron-binding 
      proteins are less sensitive to Tam-induced lysosomal damage when autophagy is 
      activated. Collectively, our data demonstrate that autophagy triggers Tam 
      resistance in breast cancer cells by favoring the lysosomal relocation of 
      overexpressed factors that restrain tamoxifen-induced lysosomal damage.
FAU - Actis, Chiara
AU  - Actis C
AUID- ORCID: 0000-0002-4465-7093
AD  - Department of Clinical and Biological Sciences, University of Turin, 10125 Turin, 
      Italy.
FAU - Muzio, Giuliana
AU  - Muzio G
AUID- ORCID: 0000-0003-2730-1957
AD  - Department of Clinical and Biological Sciences, University of Turin, 10125 Turin, 
      Italy.
FAU - Autelli, Riccardo
AU  - Autelli R
AUID- ORCID: 0000-0002-7942-5268
AD  - Department of Clinical and Biological Sciences, University of Turin, 10125 Turin, 
      Italy.
LA  - eng
GR  - Local Research Grant/University of Turin, Italy/
PT  - Journal Article
DEP - 20210312
PL  - Switzerland
TA  - Cancers (Basel)
JT  - Cancers
JID - 101526829
PMC - PMC7999102
OTO - NOTNLM
OT  - autophagy
OT  - breast cancer
OT  - endocrine resistance
OT  - iron-binding proteins
OT  - lysophagy
OT  - lysosomal membrane permeabilization
COIS- The authors declare no conflict of interest.
EDAT- 2021/04/04 06:00
MHDA- 2021/04/04 06:01
PMCR- 2021/03/12
CRDT- 2021/04/03 01:32
PHST- 2021/02/14 00:00 [received]
PHST- 2021/03/07 00:00 [revised]
PHST- 2021/03/08 00:00 [accepted]
PHST- 2021/04/03 01:32 [entrez]
PHST- 2021/04/04 06:00 [pubmed]
PHST- 2021/04/04 06:01 [medline]
PHST- 2021/03/12 00:00 [pmc-release]
AID - cancers13061252 [pii]
AID - cancers-13-01252 [pii]
AID - 10.3390/cancers13061252 [doi]
PST - epublish
SO  - Cancers (Basel). 2021 Mar 12;13(6):1252. doi: 10.3390/cancers13061252.