CA

MA

-1

MD

A-M

B-3

61

(HE

R2

+)

HC

C-1

56

9 (H

ER

2+

)

BT

47

4 (H

ER

2+

)

HS

57

8T

MD

A-M

B-4

15

(Lu

min

al)

MD

A-M

B-2

31

MD

A-M

B-4

68

MD

A-M

B-4

36

BT

20

T

MD

A-M

B-1

57

76

N

10

A

76

NF

2V

76

NE

7

T4

7D

ZR

75

-1

MC

F-7

MD

A-M

B-4

53

(HE

R2

+)

HC

C3

8

M4

A4

NM

2C

5

HC

C-1

50

0

HC

C-1

95

4

HC

C-1

42

8

HC

C-1

41

9 (H

ER

2+

)

HC

C-1

93

7

DU

44

75

HC

C-1

80

6

UA

CC

-89

3 (H

ER

2+

)

AU

56

5 (H

ER

2+

)

SK

BR

3 (H

ER

2+

)

UA

CC

89

3 (H

ER

2+

)

BT

48

3

BT

54

9

Cy

cli

n E

Actin

Cy

cli

n E

Actin

Cy

cli

n E

Actin

De

ns

ito

me

try

Un

its

Subtype

LMW-E Levels

A

B

p=

0.0

03

Supplemental Figure 1

Full Length Cyclin E Levels

Protein FC:Sen p-value

I3C SensitiveCaspase 3 (active) 1.7 3.31E-08

p53 1.6 1.77E-10S6 pS235/pS236 1.3 0.02

p21 1.3 0.000111AMPK pT172 1.3 0.00043

Smac -1.2 0.0164E-BP1 pS65 -1.2 6.38E-09

PRAS40 pT246 -1.2 0.000488eEF2K -1.3 2.52E-06B-Raf -1.3 <1.0E-15

Paxillin -1.4 5.97E-1053BP1 -1.4 1.33E-11c.Myc -1.4 4.70E-08IAP -1.5 3.24E-11

HER3 -1.6 <1.0E-15Rb pS807/S811 -1.7 <1.0E-15

AIB1(SRC-1) -1.7 4.33E-15AR -1.8 <1.0E-15

GATA3 -2.0 1.53E-08PR -3.0 <1.0E-15

ER alpha -6.3 <1.0E-15I3C Insensitive FC:InSen p-value

Src pY416 1.3 0.000467Src pY527 1.3 2.35E-09

STAT3 pY705 -1.2 1.00E-05Caspase 7 cleaved D198 -1.4 0.00317

PKC alpha -3.0 2.72E-10Both FC:Sen p-value FC:InSen p-valueSnail 2.0 3.11E-12 1.6 4.63E-06c.Jun 1.4 3.83E-07 1.2 0.000817

Cyclin E1 1.4 2.21E-13 1.3 2.22E-12GSK3 alpha pS21/beta pS9 1.3 7.73E-09 1.3 3.04E-13

IGF-1R beta -1.4 <1.0E-15 -1.4 <1.0E-15Fibronectin -1.7 0.000102 -1.4 0.0166

Supplemental Table 1

I3C Sensitive Cells p-valueNRF2-mediated Oxidative Stress Response 2.00E-10Cell Cycle: G2/M DNA Damage Checkpoint Regulation 2.14E-08Protein Ubiquitination Pathway 1.07E-07Role of BRCA1 in DNA Damage Response 3.55E-07Molecular Mechanisms of Cancer 1.20E-06PI3K/AKT Signaling 1.45E-06Role of CHK Proteins in Cell Cycle Checkpoint Control 1.78E-06p53 Signaling 2.40E-06Actin Nucleation by ARP-WASP Complex 5.75E-06Mitotic Roles of Polo-Like Kinase 1.00E-05ATM Signaling 1.00E-05Purine Metabolism 1.20E-05Aminoacyl-tRNA Biosynthesis 3.31E-05Breast Cancer Regulation by Stathmin1 3.55E-05Hereditary Breast Cancer Signaling 3.63E-05Fcγ Receptor-mediated Phagocytosis in Macrophages and Monocytes 3.98E-05Apoptosis Signaling 5.50E-05Inositol Phosphate Metabolism 6.03E-05Glioma Signaling 7.94E-05Rac Signaling 9.55E-05Pancreatic Adenocarcinoma Signaling 1.12E-04Aryl Hydrocarbon Receptor Signaling 1.23E-04Induction of Apoptosis by HIV1 1.29E-04Estrogen Receptor Signaling 1.35E-04Cell Cycle Control of Chromosomal Replication 1.78E-04

I3C Insensitive Cells p-valueNRF2-mediated Oxidative Stress Response 7.76E-0714-3-3-mediated Signaling 1.15E-05Valine, Leucine and Isoleucine Degradation 1.51E-05Integrin Signaling 2.95E-05Fcγ Receptor-mediated Phagocytosis in Macrophages and Monocytes 6.03E-05IL-8 Signaling 7.76E-05VEGF Signaling 9.77E-05One Carbon Pool by Folate 1.58E-04Virus Entry via Endocytic Pathways 1.95E-04Rac Signaling 2.24E-04Axonal Guidance Signaling 2.75E-04Actin Nucleation by ARP-WASP Complex 2.82E-04Role of Tissue Factor in Cancer 3.16E-04HER-2 Signaling in Breast Cancer 3.16E-04Actin Cytoskeleton Signaling 3.47E-04Signaling by Rho Family GTPases 3.55E-04Thrombin Signaling 4.17E-04Docosahexaenoic Acid (DHA) Signaling 4.57E-04Breast Cancer Regulation by Stathmin1 5.50E-04Glioma Signaling 5.50E-04Mechanisms of Viral Exit from Host Cells 6.46E-04Cell Cycle: G2/M DNA Damage Checkpoint Regulation 7.08E-04PI3K/AKT Signaling 7.41E-04Macropinocytosis Signaling 8.32E-04Germ Cell-Sertoli Cell Junction Signaling 1.07E-03

Supplemental Table 2

Supplemental Figure 2

IC50 (μM)

Control 490.8shAHR.1 585.0shAHR.2 570.0

MDA-MB-157

B

ControlshAHR.1shAHR.2

Actin

AhR

Control sh-AHR.1 sh-AHR.2

No

rma

lize

d A

bs

orb

an

ce

(5

90

nM

)

Log I3C concentration (μM)

D 100 250 D 100 250 D 100 250 μM

A

No

rma

lize

d A

bs

orb

an

ce

(5

90

nM

)

Log Tamoxifen concentration (μM)

A

No

rma

lize

d A

bs

orb

an

ce

(5

90

nM

)Log I3C concentration (μM)

B

ParentalTAM-R

IC50 (μM)

Parental 0.9TAM-R 5.2

IC50 (μM)

Parental 277.9TAM-R 253.1

Supplemental Figure 3

T47D

ZR75-1

MCF-7

MDA-MB-436

MDA-MB-231

MDA-MB-157

I3C (μM)

p53

Actin

- + - + - + - + I3C (250 μM)

Control sh1 sh2 sh3

MCF-7A B

p53

IC50 (μM)

Control 265.2shP53.1 254.2shP53.2 243.8shP53.3 222.3

C

MCF-7

Supplemental Figure 4N

orm

ali

zed

Ab

so

rba

nc

e (

59

0 n

M)

Log I3C concentration (μM)

ControlshP53.1shP53.2shP53.3

p53 shRNA