title: Down-regulation of caspase 3 in breast cancer: a possible mechanism for chemoresistance.
abstract: Caspase-3 is a member of the cysteine protease family, which plays a crucial role in apoptotic pathways by cleaving a variety of key cellular proteins. Caspase-3 can be activated by diverse death-inducing signals, including the chemotherapeutic agents. The purpose of this study was to determine the levels of caspase-3 expression in breast tumor samples and to determine whether alterations in its expression can affect their ability to undergo apoptosis. Primary breast tumor and normal breast parenchyma samples were obtained from patients undergoing breast surgery and the expression of caspases-3 was studied. Similarly, normal mammary epithelial cells and several established mammary cancer cell lines were studied for caspases-3 expression by reverse transcriptase-polymerase chain reaction, Northern blot analysis, and Western blot analysis. Approximately 75% of the tumor as well as morphologically normal peritumoral tissue samples lacked the caspase-3 transcript and caspase-3 protein expression. In addition, the caspases-3 mRNA levels in commercially available total RNA samples from breast, ovarian, and cervical tumors were either undetectable (breast and cervical) or substantially decreased (ovarian). Despite the complete loss of caspase-3, the expression levels of other caspases, such as caspase-8 and caspase-9, were normal in all of the tumor samples studied. The sensitivity of caspase-3-deficient breast cancer (MCF-7) cells to undergo apoptosis in response to doxorubicin and other apoptotic stimuli could be augmented by reconstituting caspase-3 expression. These results suggest that the loss of caspases-3 expression may represent an important cell survival mechanism in breast cancer patients.
authors.affiliation: Department of Bioimmunotherapy, The University of Texas MD Anderson Cancer Center, Houston, Texas, TX 77030, USA.
authors.forename: Eswaran
authors.initials: E
authors.lastname: Devarajan
authors.forename: Aysegul A
authors.initials: AA
authors.lastname: Sahin
authors.forename: Jack S
authors.initials: JS
authors.lastname: Chen
authors.forename: Raghu R
authors.initials: RR
authors.lastname: Krishnamurthy
authors.forename: Neeraj
authors.initials: N
authors.lastname: Aggarwal
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Brun
authors.forename: Anna
authors.initials: A
authors.lastname: Sapino
authors.forename: Fan
authors.initials: F
authors.lastname: Zhang
authors.forename: Dhawal
authors.initials: D
authors.lastname: Sharma
authors.forename: Xiao-He
authors.initials: XH
authors.lastname: Yang
authors.forename: Ann D
authors.initials: AD
authors.lastname: Tora
authors.forename: Kapil
authors.initials: K
authors.lastname: Mehta
mesh_terms: D001483:Base Sequence; D015152:Blotting, Northern; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000201:enzymology* / Q000473:pathology; D053148:Caspase 3; D020169:Caspases / Q000235:genetics* / Q000378:metabolism; D017931:DNA Primers; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005434:Flow Cytometry; D006801:Humans; D014407:Tumor Cells, Cultured
chemical_list: D017931:DNA Primers; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases