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dc.contributor.authorChan, Kai C
dc.contributor.authorKnox, W Fiona
dc.contributor.authorGee, Julia M
dc.contributor.authorMorris, Julie
dc.contributor.authorNicholson, Robert I
dc.contributor.authorPotten, Christopher S
dc.contributor.authorBundred, Nigel J
dc.date.accessioned2009-10-05T15:00:51Z
dc.date.available2009-10-05T15:00:51Z
dc.date.issued2002-01-01
dc.identifier.citationEffect of epidermal growth factor receptor tyrosine kinase inhibition on epithelial proliferation in normal and premalignant breast. 2002, 62 (1):122-8 Cancer Res.en
dc.identifier.issn0008-5472
dc.identifier.pmid11782368
dc.identifier.urihttp://hdl.handle.net/10541/83544
dc.description.abstractThe factors controlling epithelial proliferation in ductal carcinoma in situ (DCIS) are unclear. Antiestrogens are effective in the prevention of the majority of estrogen receptor-positive, but not estrogen receptor (ER)-negative breast cancers, which suggests that other factor(s) are promoting proliferation in ER-negative DCIS. Mutated or overexpressed tyrosine kinases are frequently associated with tumor development. Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that is involved with mitogenesis and is expressed in ER-negative DCIS. We hypothesized that EGFR is central in driving proliferation in ER-negative/EGFR-positive DCIS. The purpose of this study was to establish whether the EGFR tyrosine kinase inhibitor (EGFR-TKI), ZD1839 (Iressa), can reduce epithelial proliferation and increase apoptosis in EGFR-positive DCIS. Breast tissue from 16 women undergoing surgery for DCIS were implanted into 16-32 immunosuppressed mice/experiment (8 xenografts/mouse). Treatment commenced 2 weeks after implantation and consisted of once daily oral gavage with ZD1839 at doses ranging from 10 to 200 mg/kg for 14-28 days; appropriate controls were present. Xenografts were removed on days 14, 21, 28, and 42 after implantation and then assessed for proliferation (LI) by Ki67 immunostaining and apoptosis index (AI) by morphology. All Ps reported are two-sided. Overall, a 56% reduction in epithelial proliferation was seen with Iressa in EGFR-positive DCIS. EGFR-TK inhibition compared with vehicle controls resulted in a fall in Geometric Mean Labeling Index (LI) after 14 days (day 28) of treatment both in ER-negative/EGFR-positive DCIS [6.5% interquartile range (IQR, 3.8-11.1) versus 13.9% (IQR, 12.0-16.3%); F(1,3) = 103; P = 0.002] and ER-positive/EGFR-positive DCIS [4.6% (IQR, 3.9-5.2%) versus 11.7% (IQR, 9.2-15.5); F(1,2) = 32.3; P = 0.03]. EGFR-TK inhibition had similar effects on the "at risk" normal breast epithelium adjacent to DCIS in the treated epithelium LI day 28 [ZD1839 2.2% (IQR, 1.7-3.3%) compared with control 3.8% (IQR, 2.4-5.4%); F(1,14) = 29.2; P = 0.00009] and in addition increased epithelial apoptotic index at day 21 [ZD1839 0.38 (0.23-0.83) compared with control 0.19 (0.1-0.25); F(1,6) = 12.2; P = 0.013]. The effect on epithelial proliferation was still significant after 28 days of treatment [for both DCIS (F1,29) = 24; P = 0.039 and normal breast F(1,6) = 47.3; P = 0.0005]. EGFR-TK inhibition with ZD1839 offers a novel approach to the treatment of EGFR-positive DCIS, regardless of ER status, and provides a potential new chemopreventative approach in patients at high risk of breast cancer.
dc.language.isoenen
dc.subjectBreast Canceren
dc.subjectXenograft Model Antitumour Assaysen
dc.subject.meshAnimals
dc.subject.meshAntineoplastic Agents
dc.subject.meshApoptosis
dc.subject.meshBreast
dc.subject.meshBreast Neoplasms
dc.subject.meshCarcinoma in Situ
dc.subject.meshCarcinoma, Ductal, Breast
dc.subject.meshCell Division
dc.subject.meshDown-Regulation
dc.subject.meshEnzyme Inhibitors
dc.subject.meshFemale
dc.subject.meshHumans
dc.subject.meshMAP Kinase Signaling System
dc.subject.meshMice
dc.subject.meshMice, Inbred BALB C
dc.subject.meshMice, Nude
dc.subject.meshMitogen-Activated Protein Kinase 1
dc.subject.meshMitogen-Activated Protein Kinase 3
dc.subject.meshMitogen-Activated Protein Kinases
dc.subject.meshPrecancerous Conditions
dc.subject.meshQuinazolines
dc.subject.meshReceptor, Epidermal Growth Factor
dc.subject.meshXenograft Model Antitumor Assays
dc.titleEffect of epidermal growth factor receptor tyrosine kinase inhibition on epithelial proliferation in normal and premalignant breast.en
dc.typeArticleen
dc.contributor.departmentDepartment of Surgery, University Hospital of South Manchester, United Kingdom.en
dc.identifier.journalCancer Researchen
html.description.abstractThe factors controlling epithelial proliferation in ductal carcinoma in situ (DCIS) are unclear. Antiestrogens are effective in the prevention of the majority of estrogen receptor-positive, but not estrogen receptor (ER)-negative breast cancers, which suggests that other factor(s) are promoting proliferation in ER-negative DCIS. Mutated or overexpressed tyrosine kinases are frequently associated with tumor development. Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that is involved with mitogenesis and is expressed in ER-negative DCIS. We hypothesized that EGFR is central in driving proliferation in ER-negative/EGFR-positive DCIS. The purpose of this study was to establish whether the EGFR tyrosine kinase inhibitor (EGFR-TKI), ZD1839 (Iressa), can reduce epithelial proliferation and increase apoptosis in EGFR-positive DCIS. Breast tissue from 16 women undergoing surgery for DCIS were implanted into 16-32 immunosuppressed mice/experiment (8 xenografts/mouse). Treatment commenced 2 weeks after implantation and consisted of once daily oral gavage with ZD1839 at doses ranging from 10 to 200 mg/kg for 14-28 days; appropriate controls were present. Xenografts were removed on days 14, 21, 28, and 42 after implantation and then assessed for proliferation (LI) by Ki67 immunostaining and apoptosis index (AI) by morphology. All Ps reported are two-sided. Overall, a 56% reduction in epithelial proliferation was seen with Iressa in EGFR-positive DCIS. EGFR-TK inhibition compared with vehicle controls resulted in a fall in Geometric Mean Labeling Index (LI) after 14 days (day 28) of treatment both in ER-negative/EGFR-positive DCIS [6.5% interquartile range (IQR, 3.8-11.1) versus 13.9% (IQR, 12.0-16.3%); F(1,3) = 103; P = 0.002] and ER-positive/EGFR-positive DCIS [4.6% (IQR, 3.9-5.2%) versus 11.7% (IQR, 9.2-15.5); F(1,2) = 32.3; P = 0.03]. EGFR-TK inhibition had similar effects on the "at risk" normal breast epithelium adjacent to DCIS in the treated epithelium LI day 28 [ZD1839 2.2% (IQR, 1.7-3.3%) compared with control 3.8% (IQR, 2.4-5.4%); F(1,14) = 29.2; P = 0.00009] and in addition increased epithelial apoptotic index at day 21 [ZD1839 0.38 (0.23-0.83) compared with control 0.19 (0.1-0.25); F(1,6) = 12.2; P = 0.013]. The effect on epithelial proliferation was still significant after 28 days of treatment [for both DCIS (F1,29) = 24; P = 0.039 and normal breast F(1,6) = 47.3; P = 0.0005]. EGFR-TK inhibition with ZD1839 offers a novel approach to the treatment of EGFR-positive DCIS, regardless of ER status, and provides a potential new chemopreventative approach in patients at high risk of breast cancer.


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