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