molecular switching of dcis to invasive carcinomas … · 2014-06-18 · normal hyperplasia dcis...
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MOLECULAR SWITCHING OF DCIS TO INVASIVE CARCINOMAS BY CCR2 CHEMOKINE
RECEPTORS
Nikki Cheng, Ph.D Department of Pathology and Laboratory Medicine University of Kansas Medical Center Kansas City, KS 66160
No Invasion
Invasion
DCIS (non-lethal) IDC (potentially lethal)
Normal Hyperplasia DCIS IDC Metastasis Time (Decades in most cases)
• Ductal carcinoma in situ (DCIS) is the most common form of non-invasive cancer (50,000 cases/year in the US)
• better methods in screening and detection, but no way to predict development of IDC
• patients may face unnecessary surgery or radiation treatment for DCIS, or may be undertreated.
• 20% of patients treated for DCIS experience relapse with more aggressive cancer
Goals: 1) identify the key factors that lead to invasive breast cancers, 2) screen for expression of these proteins in patients
• Research question: what are the key factors that promote the development of invasive breast cancer?
• We propose that CCR2, a chemokine receptor protein is a key factor.
avoid overtreating patients, and design more effective drugs to prevent or treat invasive breast cancer.
CCR2 chemokine signaling and inflammation
• Immune response against bacterial infections
• Wound healing
• Diabetes/obesity
• Chronic inflammation: Rheumatoid arthritis
Macrophages
CCL2
CCR2
CCR2 belongs to family of molecules called chemokine receptors that regulate immune cell recruitment during wound healing, infection, and inflammatory diseases.
Overexpression of CCR2 in breast cancer cells DCIS Normal IDC Grade2
Low CCR2, n=1335 High CCR2, n=1325
HR= 0.77(0.62-0.96) Logrank P value=0.022
0 5 10 15 20 25 Time (Years)
1.0
0.8
0.6
0.4
0.2
0.0
Pro
babi
lity
DM
FS
CCL2 expression is significantly increased in DCIS
0
0.5
1
1.5
2
2.5
3
Normal stroma DCIS stroma
Fold
RN
A ex
pres
sion
DCIS
The MIND model of DCIS
F. Behbod et al An intraductal human-in-mouse transplantation model mimics the subtypes of ductal carcinoma in situ. Breast Cancer Research 2009 vol 11. no5
DCIS.com vs. Sum225 MIND models
DCIS.com
Sum225
6 weeks 10 weeks
invasive
Non-invasive
F. Behbod et al An intraductal human-in-mouse transplantation model mimics the subtypes of ductal carcinoma in situ. Breast Cancer Research 2009 vol 11. no5
CC
L2
CC
R2
DCIS.com Sum225 Patient DCIS
anti-rabbit anti-goat
Control
Increased CCL2 and CCR2 expression in DCIS.com carcinomas is similar to high grade DCIS from patient samples
Gene silencing of CCR2 inhibits breast cancer cell invasion
DCIS.com or Sum225
Day 11
Invasion Growth
Survival/time
DCIS.com Sum225
DCIS.com/CCR2-
CCR2 gene silencing
RNA
siRNA
DNA CCR2
Model: Expression of CCR2 in breast cancer cells may serve as a trigger for invasive breast cancers
DCIS DCIS with IDC
Future Directions
• Overexpress CCR2 in Sum225 cells/silence CCR2 in DCIS.com cells • Examine DCIS progression in the MIND model
• Examine molecular mechanisms of CCR2 signaling in breast cancer cells using 3D cell culture models • Invasion • Survival
Acknowledgements KU Medical Center
Dept. Pathology Fang Fan, M.D, Ph.D
Cores FACS BSR LAR
Cheng Lab Wei Bin Fang, Ph.D Min Yao, M.Sci An Zou Benford Mafuvadze, Ph.D Mike Portsche
Funding Susan G. Komen Career Catalyst Award CCR14261859
Fariba Behbod, Pharm.D, Ph.D Kelli Valdez, Ph.D Yan Hong Mentors: Danny Welch, Ph.D Roy Jensen, M.D Michael Soares, Ph.D