Figure 1 A B C - + ERα patients Luminal A+B Adjuvant Endocrine Therapy

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Figure 1 A B C - + ERα patients Luminal A+B Adjuvant Endocrine Therapy Biopsies from patient first relapse SERM=Tamoxifen(n=30) AI=Letrozole/Anastrozole (n=37) Copy Number CYP19A1/ESR1TM Normalizer:TERTTM FISH (15q21.2 locus) Normalizer FISH (15 α-Satellite) Primary Surgical Material TTR=79 months (16-181) TTR=44 months (3-104) Discovery Dataset A Relapse Metastatic Biopsy 15 yrs. 8 TAM 6 1/30 CYP19A1 4/30 ESR1 4 3 2 Copy Number Gain 0.5 Copy Number Loss Copy Number (TAQMAN) normalized to normal matched tissue 1t 2t 4t 5t 6t 10t 11t 12t 13t 14t 15t 17t 19t 20t 21t 22t 23t 24t 26t 27t 28t 30t 32t 33t 35t 36t 37t 40t 42t 43t 8 Patient # CYP19A1 ESR1 AI 6/37 9/37 6 4 3 2 0.5 2t 4t 5t 7t 8t 9t 10t 11t 12t 13t 14t 15t 17t 18t 19t 20t 21t 22t 24t 25t 26t 28t 29t 30t 32t 33t 34t 35t 36t 37t 38t 39t 41t 43t 46t 47t 49t Patient # B C ERα patients Luminal A+B SERM= Tam (13) AI=Let/Ana (17) Copy NumberTM CYP19A1/ESR1/ NormalizerTM TERT/RNASEP/GABRB3 FISH (15q21.2 locus) Normalizer FISH (15 α-Satellite) Primary Relapse Validation Dataset TTR=69 months TTR=54 months PDXs Dataset Pleural effusion/Ascites 15 yrs. TAM 8 1/19 CYP19A1/TERT 6 CYP19A1/RNASEP 8 4 CYP19A1/TERT 3 6 CYP19A1/RNASEP 2 Copy Number (TAQMAN) normalized to normal matched tissue 0.5 4 Copy Number (TAQMAN) normalized to normal N19 4t-v 5t-v 12t-v 25t-v 16t-v 3t-v 1t-v 11t-v 31t-v 35t-v 24t-v 36t-v 2t-v 63t-v 65t-v 68t-v 70t-v 73t-v 64t-v 3 2 15 AI 0.5 6/19 CYP19A1/TERT 10 CYP19A1/RNASEP BA-8 BPE-12 BA-11 BA-1 CTC288 BPE2-0 CTC223 5 MaCa-3366 3 2 0.5 History of AI treatment - + NA 26t-v 57t-v 58t-v 60t-v 62t-v 49t-v 46t-v 39t-v 50t-v 40t-v 41t-v 44t-v 48t-v 54t-v 27t-v 13t-v 59t-v 78t-v 80t-v

AROMATASE INHIBITORS Discovery Dataset Figure 2 A 11T 20T 11P 20P 33T 12T 33P 12P Metastasis Primary AROMATASE INHIBITORS Discovery Dataset 15α Satellite CYP19A1 B C 12P 33P 33T 12T TP53 48% ESR1 19% GATA3 34% MAP3K1 20% PIK3CA 44% 32% 27% TAM n=22 AI n=29 ID Ratio 11T 3.00 11P 1.49 20T 5.8 20P 1.38 33T 2.97 33P 1.22 12T 2.68 12P 1.27 AI n=4 D TAMOXIFEN PI3K 1 1 1 1 1 1 4 MAP3K1 1 1 6 1 1 1 8 GATA3 1 1 1 1 1 1 TP53 1 1 5 2 1 3 4 ESR1 1 4 1 1 1 2 Patient ID 1t 2t 4t 5t 6t 10t 11t 12t 13t 14t 15t 17t 19t 20t 21t 22t 24t 26t 27t 23t 28t 30t 32t 33t 35t 36t 37t 40t 42t 43t AI PI3K 1 6 2 2 1 9 9 1 1 2 1 2 25 MAP3K1 1 7 18 1 2 27 GATA3 1 2 1 7 5 3 1 1 1 4 TP53 1 1 1 1 1 1 8 4 2 3 1 4 14 1 ESR1 5 6 1 2 1 11 Patient ID 2t 4t 5t 7t 8t 9t 10t 11t 12t 13t 14t 15t 17t 18t 19t 20t 22t 24t 25t 21t 26t 28t 29t 30t 32t 33t 34t 35t 36t 37t 38t 39t 41t 43t 46t 47t 49t ION reporter calls Sample not available N TP53 truncating SNVs Not mutated ERα activating SNVs N Mutated (missense/nonsense/indels/HIGH confidence) N ERα potential activating SNVs

Figure 3 A B C E D F CYP19A1 RT-qPCR single cell RNA-FISH CYP19A1 WB DNA FISH A B MCF7 cells LTED cells CYP19A1 ESR1 6 Copy Number(TAQMAN) normalized to MCF10A Copy Number Gain 3 Copy Number CYP19A1/ESR1TM Normalizer:TERTTM .5 CYP19A1 15α Satellite MCF7 LTED Copy Number Loss C CYP19A1 RT-qPCR E single cell RNA-FISH Frequency mRNA per cell (#) 5 10 15 20 0.2 0.4 0.6 0.8 20 Cyp19A1 mRNA 1 Cyp19A1 mRNA **** 20 INTRON EXON 10 Fold change over MCF7 MCF7 MCF7T MCF7F LTED LTEDT LTEDF MCF7 LTED MCF7T MCF7F LTEDT LTEDF D CYP19A1 WB CYP19A1 50kDA ACTIN MCF7 LTED MCF7T MCF7F LTEDT LTEDF F Transcriptional activation estrogen target genes mock E2 mock And. 40 * 3 CYP19A1wt MCF7 30 2 20 10 1 TFF1 EGR3 CA12 TFF1 EGR3 CA12 mRNA fold change vs. mock 8 * mock E2 mock And. 6 8 * 20 4 * * 6 LTED CYP19A1amp 15 * 2 4 10 * 5 2 * AND - + - + - + AI TFF1 EGR3 CA12 TFF1 EGR3 CA12 TFF1 EGR3 CA12

Figure 4 A B C D E F G TFF1 TMPRSS3 LTED MCF7 0.03 > > > LTED CCND1 0.03 > > > > 51974 binding sites LTED RPKM MCF7 MYC 0.03 > 300 LTED 300 MCF7 -2.5kb +2.5kb 1 B C D siC 2 MCF7 2 LTED LTED siCYP19A1-1 siCYP19A1-2 100 MTT (abs 595) * * MTT (abs 595) 1 1 * * * ** * Proliferation (SRB) (vs. DMSO/siC) 1 1uM mock 1uM 100nM 10uM 25uM 50uM 75uM mock 100uM 175uM 200uM 225uM 250uM 100nM 10uM 25uM 50uM 75uM 100uM mock 1uM 5uM 100nM 500nM 10uM 50uM Letrozole (concentration) E MCF7 F TTFR +E2 100 4 H.R.= 0.43 (0.22-0.82) p (Log-Rank= 0.0112) -E2 3 * * * * * * * * 2 50 CYP19A1amp Percent Relapse-Free SRB (CYP1A1 o.e/WT.) CYP19A1wt 1 50 100 mock 50nM 1uM 5uM 100nM 500nM 10uM 50uM G TAM adjuvant AI adjuvant Primary Metastatic Peripheral Aromatase activity Local Aromatase activity Treatment strategy Increased Cholesterol biosynthesis GENETIC EPIGENETIC