PMID- 22217342
OWN - NLM
STAT- MEDLINE
DCOM- 20120320
LR  - 20220408
IS  - 1471-2407 (Electronic)
IS  - 1471-2407 (Linking)
VI  - 12
DP  - 2012 Jan 4
TI  - HIF-1 activation induces doxorubicin resistance in MCF7 3-D spheroids via 
      P-glycoprotein expression: a potential model of the chemo-resistance of invasive 
      micropapillary carcinoma of the breast.
PG  - 4
LID - 10.1186/1471-2407-12-4 [doi]
AB  - BACKGROUND: Invasive micropapillary carcinoma (IMPC) of the breast is a distinct 
      and aggressive variant of luminal type B breast cancer that does not respond to 
      neoadjuvant chemotherapy. It is characterized by small pseudopapillary clusters 
      of cancer cells with inverted cell polarity. To investigate whether 
      hypoxia-inducible factor-1 (HIF-1) activation may be related to the drug 
      resistance described in this tumor, we used MCF7 cancer cells cultured as 3-D 
      spheroids, which morphologically simulate IMPC cell clusters. METHODS: HIF-1 
      activation was measured by EMSA and ELISA in MCF7 3-D spheroids and MCF7 
      monolayers. Binding of HIF-1alpha to MDR-1 gene promoter and modulation of 
      P-glycoprotein (Pgp) expression was evaluated by ChIP assay and FACS analysis, 
      respectively. Intracellular doxorubicin retention was measured by 
      spectrofluorimetric assay and drug cytotoxicity by annexin V-FITC measurement and 
      caspase activity assay. RESULTS: In MCF7 3-D spheroids HIF-1 was activated and 
      recruited to participate to the transcriptional activity of MDR-1 gene, coding 
      for Pgp. In addition, Pgp expression on the surface of cells obtained from 3-D 
      spheroids was increased. MCF7 3-D spheroids accumulate less doxorubicin and are 
      less sensitive to its cytotoxic effects than MCF7 cells cultured as monolayer. 
      Finally, HIF-1alpha inhibition either by incubating cells with 
      3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole (a widely used HIF-1alpha inhibitor) 
      or by transfecting cells with specific siRNA for HIF-1alpha significantly decreased 
      the expression of Pgp on the surface of cells and increased the intracellular 
      doxorubicin accumulation in MCF7 3-D spheroids. CONCLUSIONS: MCF7 breast cancer 
      cells cultured as 3-D spheroids are resistant to doxorubicin and this resistance 
      is associated with an increased Pgp expression in the plasma membrane via 
      activation of HIF-1. The same mechanism may be suggested for IMPC drug 
      resistance.
FAU - Doublier, Sophie
AU  - Doublier S
AD  - Department of Genetics, Biology and Biochemistry, University of Turin, Via 
      Santena, 5/bis, 10126 Turin, Italy. sophie.doublier@unito.it
FAU - Belisario, Dimas C
AU  - Belisario DC
FAU - Polimeni, Manuela
AU  - Polimeni M
FAU - Annaratone, Laura
AU  - Annaratone L
FAU - Riganti, Chiara
AU  - Riganti C
FAU - Allia, Elena
AU  - Allia E
FAU - Ghigo, Dario
AU  - Ghigo D
FAU - Bosia, Amalia
AU  - Bosia A
FAU - Sapino, Anna
AU  - Sapino A
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120104
PL  - England
TA  - BMC Cancer
JT  - BMC cancer
JID - 100967800
RN  - 0 (ATP Binding Cassette Transporter, Subfamily B, Member 1)
RN  - 0 (Annexins)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Hypoxia-Inducible Factor 1)
RN  - 80168379AG (Doxorubicin)
RN  - EC 3.4.22.- (Caspases)
SB  - IM
MH  - ATP Binding Cassette Transporter, Subfamily B, Member 1/*metabolism
MH  - Annexins/analysis
MH  - Antineoplastic Agents/*pharmacology
MH  - *Breast Neoplasms/drug therapy/metabolism
MH  - *Carcinoma, Papillary/drug therapy/metabolism
MH  - Caspases/analysis
MH  - Doxorubicin/*pharmacology
MH  - Drug Resistance, Neoplasm/*physiology
MH  - Female
MH  - Humans
MH  - Hypoxia-Inducible Factor 1/*metabolism
MH  - Spheroids, Cellular
MH  - Tumor Cells, Cultured
PMC - PMC3262753
EDAT- 2012/01/06 06:00
MHDA- 2012/03/21 06:00
PMCR- 2012/01/04
CRDT- 2012/01/06 06:00
PHST- 2011/04/14 00:00 [received]
PHST- 2012/01/04 00:00 [accepted]
PHST- 2012/01/06 06:00 [entrez]
PHST- 2012/01/06 06:00 [pubmed]
PHST- 2012/03/21 06:00 [medline]
PHST- 2012/01/04 00:00 [pmc-release]
AID - 1471-2407-12-4 [pii]
AID - 10.1186/1471-2407-12-4 [doi]
PST - epublish
SO  - BMC Cancer. 2012 Jan 4;12:4. doi: 10.1186/1471-2407-12-4.