Companion PowerPoint slide set Obesity-associated breast cancer

risk: a role for epigenetics?

This work was funded by the National Institute of Environmental

Health Sciences (P42ES005948; P30 ES010126).

Dr. Liza Makowski

Studies Basal-like Breast Cancer (BBC)

• Aggressive cancer

• No specific drug therapies

• Short survival time if it spreadsbeyond 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 ratecompared to lean mice

Nu

mb

er

of

we

eks

u

nti

l tu

mo

r fo

rmat

ion

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+

sta

inin

gin

No

rma

l M

am

ma

ry

*

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-MetB

BC

Tu

mo

r ce

ll lin

e

BB

C T

um

or

cell

line

+ C

M

BB

C T

um

or

cell

line

+

mH

GF

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.