Please use this identifier to cite or link to this item: https://doi.org/10.18632/oncotarget.10894
Title: High expression of intratumoral stromal proteins is associated with chemotherapy resistance in breast cancer
Authors: Wang, T 
Srivastava, S 
Hartman, M 
Buhari, S.A 
Chan, C.-W 
Iau, P
Khin, L.W 
Wong, A 
Tan, S.-H 
Goh, B.-C 
Lee, S.-C 
Keywords: alpha smooth muscle actin
beta1 integrin
docetaxel
doxorubicin
estrogen receptor
FN protein
mammalian target of rapamycin
oncoprotein
SPARC protein
THBS1 protein
TNC protein
unclassified drug
beta1 integrin
MTOR protein, human
target of rapamycin kinase
tenascin
thrombospondin 1
thrombospondin-1, human
Article
breast cancer
breast surgery
cancer adjuvant therapy
cancer growth
cancer resistance
cancer survival
clinical feature
cohort analysis
controlled study
drug efficacy
female
human
human tissue
immunohistochemistry
major clinical study
MCF 7 cell line
multiple cycle treatment
outcome assessment
overall survival
phase 2 clinical trial
prediction
protein determination
protein expression
protein function
randomized controlled trial
tumor biopsy
upregulation
adult
aged
breast tumor
chemistry
drug resistance
middle aged
mortality
pathology
physiology
signal transduction
tumor cell line
Adult
Aged
Breast Neoplasms
Cell Line, Tumor
Drug Resistance, Neoplasm
Female
Humans
Integrin beta1
Middle Aged
Signal Transduction
Tenascin
Thrombospondin 1
TOR Serine-Threonine Kinases
Issue Date: 2016
Citation: Wang, T, Srivastava, S, Hartman, M, Buhari, S.A, Chan, C.-W, Iau, P, Khin, L.W, Wong, A, Tan, S.-H, Goh, B.-C, Lee, S.-C (2016). High expression of intratumoral stromal proteins is associated with chemotherapy resistance in breast cancer. Oncotarget 7 (34) : 55155-55168. ScholarBank@NUS Repository. https://doi.org/10.18632/oncotarget.10894
Abstract: We studied the changes of intratumoral stromal proteins including THBS1, TNC, FN, SPARC and a-SMA, following neoadjuvant chemotherapy. The underlying mechanisms by which THBS1 and TNC regulated resistance to docetaxel were further studied using functional studies. 100 patients with newly diagnosed breast cancer were treated with alternating sequential doxorubicin and docetaxel. Immunohistochemistry (IHC) staining for stromal proteins was performed on pre- and post-treatment core biopsies respectively. THBS1 and TNC were further validated with IHC in an independent cohort of 31 patients. A high baseline combined expression score of the 5 stromal proteins predicted independently for poor progression-free (HRadjusted 2.22, 95% CI 1.06-4.64) and overall survival (HRadjusted 5.94, 95% CI 2.25-15.71). After 1-2 cycles of chemotherapy, increased expression of THBS1, TNC, FN, SPARC and a-SMA was seen in patients with subsequent pathological lymph node involvement at surgery. Increased expression of THBS1 and TNC compared to baseline was also seen in intrinsically resistant tumors, but not in sensitive ones. Both THBS1 and TNCassociated chemoresistance were confirmed in an independent validation cohort. Exogenous THBS1 and TNC protected MCF-7 cells against proliferation inhibition induced by docetaxel through activating integrin ß1/mTOR pathway. Thus, upregulation of THBS1, TNC, FN, SPARC and a-SMA following neoadjuvant chemotherapy was associated with chemotherapy resistance in breast cancer patients. Functional studies showed THBS1 and TNC to mediate chemoresistance through the integrin ß1/mTOR pathway, suggesting that therapies targeting integrin ß1/mTOR pathway may be a promising strategy to overcome chemotherapy resistance.
Source Title: Oncotarget
URI: https://scholarbank.nus.edu.sg/handle/10635/174109
ISSN: 19492553
DOI: 10.18632/oncotarget.10894
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