PMID- 18072255
OWN - NLM
STAT- MEDLINE
DCOM- 20080325
LR  - 20170824
IS  - 0008-543X (Print)
IS  - 0008-543X (Linking)
VI  - 112
IP  - 3 Suppl
DP  - 2008 Feb 1
TI  - Preclinical modeling of endocrine response and resistance: focus on aromatase 
      inhibitors.
PG  - 679-688
LID - 10.1002/cncr.23191 [doi]
AB  - The authors developed a breast cancer intratumoral aromatase model system to 
      compare the antitumor efficacy of several aromatase inhibitors (AIs) and 
      antiestrogens (AEs). Although the AI letrozole caused sustained growth 
      inhibition, tumors eventually began to grow, even when treatment was maintained. 
      For the current study, the mechanisms of resistance to letrozole during the 
      course of treatment were investigated. Estrogen receptor alpha (ER-alpha) levels 
      decreased below control levels in letrozole-resistant tumors. The decrease was 
      simultaneous to an increase in phosphorylation of ER-alpha and an unaltered 
      expression of progesterone receptor (PgR). Expression levels of HER-2, activated 
      (phosphorylated) SHC-adaptor protein (p-Shc), growth factor receptor-bound 
      protein 2 (Grb-2), p-Raf, phosphorylated mitogen-activated protein kinase kinase 
      1/2 (p-Mekl/2), and phosphorylated mitogen-activated protein kinase (p-MAPK) were 
      increased. When cells isolated from letrozole-resistant tumors (LTLTCa cells) 
      were treated with inhibitors of the HER-2 signaling pathway, ER-alpha expression 
      and estradiol-stimulated transactivation was restored. The HER-2 blocker 
      trastuzumab also restored the sensitivity of LTLTCa cells to AIs and AEs. These 
      findings suggested that there is crosstalk between ER and HER-2 signaling. To 
      prevent activation of the HER-2 pathway and resistance to AIs, mice were treated 
      with a combination of AIs and the ER down-regulator fulvestrant. There was no 
      increase in HER-2 or p-MAPK expression, and tumor growth was inhibited 
      significantly. When trastuzumab was added to unresponsive tumors under letrozole 
      treatment, it significantly inhibited tumors growth compared with switching to 
      trastuzumab alone. However, the trastuzumab plus letrozole combination was more 
      effective than letrozole alone only in refractory breast tumors. These results 
      suggested that blocking both ER and HER-2 signaling may delay the development of 
      resistance to AIs in patients with recurrent breast cancer.
CI  - Cancer 2008. (c) 2007 American Cancer Society.
FAU - Macedo, Luciana F
AU  - Macedo LF
AD  - Department of Pharmacology and Experimental Therapeutics, University of Maryland 
      School of Medicine, and the Greenebaum Cancer Center, Baltimore, Maryland.
FAU - Sabnis, Gauri
AU  - Sabnis G
AD  - Department of Pharmacology and Experimental Therapeutics, University of Maryland 
      School of Medicine, and the Greenebaum Cancer Center, Baltimore, Maryland.
FAU - Brodie, Angela
AU  - Brodie A
AD  - Department of Pharmacology and Experimental Therapeutics, University of Maryland 
      School of Medicine, and the Greenebaum Cancer Center, Baltimore, Maryland.
LA  - eng
GR  - CA-62483/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PL  - United States
TA  - Cancer
JT  - Cancer
JID - 0374236
RN  - 0 (Antineoplastic Agents, Hormonal)
RN  - 0 (Aromatase Inhibitors)
RN  - 0 (Estrogen Receptor alpha)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents, Hormonal/*therapeutic use
MH  - Aromatase Inhibitors/*therapeutic use
MH  - Breast Neoplasms/*drug therapy/pathology
MH  - *Disease Models, Animal
MH  - *Drug Resistance, Neoplasm
MH  - Estrogen Receptor alpha/metabolism
MH  - Humans
MH  - Xenograft Model Antitumor Assays
EDAT- 2007/12/12 09:00
MHDA- 2008/03/26 09:00
CRDT- 2007/12/12 09:00
PHST- 2007/12/12 09:00 [pubmed]
PHST- 2008/03/26 09:00 [medline]
PHST- 2007/12/12 09:00 [entrez]
AID - 10.1002/cncr.23191 [doi]
PST - ppublish
SO  - Cancer. 2008 Feb 1;112(3 Suppl):679-688. doi: 10.1002/cncr.23191.