Companion PowerPoint slide set Obesity-associated breast cancer risk: a role for epigenetics?

This teacher slide set was created by Dana Haine, MS, of the UNC Center for Environmental Health

and Susceptibility, which is funded by the National Institute of Environmental Health

Sciences (P30-ES010126).

Dr. Liza Makowski

Studies Basal-like Breast Cancer (BBC)• Aggressive cancer • No specific drug therapies• Short survival time if it spreads

beyond breast tissue (metastasis)• More prevalent in young

pre-menopausal women• More prevalent in African Americans• Obesity is a risk factor for all breast

cancers

Obesity causes BBC tumors to form at a faster rate compared to lean mice

Num

ber o

f wee

ks

until

tum

or fo

rmati

on

Fat-fed (Lean)

Fat-fed (obese)

Cross-section of mammary (milk) duct

http://www.womenshealth.gov/breast-cancer/what-is-breast-cancer/

Inside (lumen) of milk duct

Label epithelial cells, fat cells and fibroblasts on the diagram below:

Epithelial Cells of Milk Duct

Inside (lumen) of milk duct

Fibroblasts

Adipocytes (Fat cells)

Immune cells are also present but are not shown in order to simplify schematic of the stroma.

Stroma of mammary tissue

microenvironment

Cancer & the microenvironment

The microenvironment (“soil”) surrounding a cell (“seed”)

plays a role in tumor formation.

HEALTHY CELL CANCER CELL

“How does obesity alter the microenvironment in breast cancer?”

Liza Makowski:

Cell to cell communication HGF-cMET paracrine signaling

HGF

C-met receptor

Adapted from Melissa Troester/Patricia Casbas-Hernandez @ UNC

Cell to cell communication HGF-cMET paracrine signaling

HGF

cMET receptor

Promotes Cell

Division

Promotes motility

(leads to Metastasis)

Promotes growth of

blood vessels to supply

tumor

Prevents cell death

Melissa Troester/Patricia Casbas-Hernandez @ UNC

PHGF

C-met

Sundaram, S., Makowski, L., et. al. Cancer Prevention Research (Under Review, 2012)

Obesity increases levels of HGF mRNA and protein in normal mammary tissue

10% 45% 60%0.0

0.5

1.0

1.5

2.0

Diets

OD

x %

HG

F+ s

tain

ing

in N

orm

al M

amm

ary

*

Lean Mice

Obese Mice

Normal

Cancer-associated

Isolate Fibroblasts

CultureFibroblasts

HGF Secretion

HGF Secretion

HGF Secretion

HGF Secretion

Measure

Ex vivo cell culture model

Cell Division

HGF secretion in cultured cells

Lean Mice

Obese Mice

Normal

Cancer-associated

Isolate Fibroblasts

CultureFibroblasts

HGF Secretion

Analysis of c-Met protein levels in BBC tumor cell line

C.

c-Met

Control

Phospho-c-MetBB

C Tu

mor

cel

l lin

e

BBC

Tum

or c

ell l

ine

+ CM

BBC

Tum

or c

ell l

ine

+

mHG

F

Fat cell Fibroblast

HGFSecretion

c-Met activation

Cancer formation

“How does obesity alter the microenvironment in breast cancer?”

Microenvironment

Signal

Epithelial cell

Conclusion: growth factor signaling pathway (HGF/cMet) was upregulated with obesity.