Multimodal Assessment of Estrogen Receptor mRNA Profiles to Quantify Estrogen Pathway Activity in Breast Tumors Anita Muthukaruppan, Annette Lasham,

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Multimodal Assessment of Estrogen Receptor mRNA Profiles to Quantify Estrogen Pathway Activity in Breast Tumors Anita Muthukaruppan, Annette Lasham, Kathryn J. Woad, Michael A. Black, Cherie Blenkiron, Lance D. Miller, Gavin Harris, Nicole McCarthy, Michael P. Findlay, Andrew N. Shelling, Cristin G. Print Clinical Breast Cancer Volume 17, Issue 2, Pages 139-153 (April 2017) DOI: 10.1016/j.clbc.2016.09.001 Copyright © 2016 The Author(s) Terms and Conditions

Figure 1 Assessment of ESR1 (Gene Encoding Estrogen Receptor [ER]-α Protein) mRNA Expression After Small Interfering RNA (siRNA) Knockdown in MCF7 Cells. (A) Log2 Expression Levels of ESR1 mRNA Measured by Microarray From Hybridization to Probe Set 205225_at. Each Biologic Sample Was Assayed in Triplicate. (B) Normalized Measurement of ESR1 mRNA Levels in Untransfected, Control siRNA- or ESR1 siRNA-Transfected MCF7 Cells Using Reverse Transcription Quantitative Polymerase Chain Reaction. (C) Log2 ESR1 mRNA Expression Levels Shown as Percent Rank (Percentile of Expression) in MCF7 Cells Transfected With siRNA Control (Circles) or ESR1 siRNA (Crosses) Were Plotted With All Breast Tumors (Sorted by Increasing Percent Rank of ESR1 Expression) and Shown Separately as ER− and ER+ Tumors (by Immunohistochemistry), and (D) Luminal A Breast Tumors (Sorted by Increasing Percent Rank of ESR1 Expression) Abbreviations: CON = control; KD = knockdown; UNT = untreated. Clinical Breast Cancer 2017 17, 139-153DOI: (10.1016/j.clbc.2016.09.001) Copyright © 2016 The Author(s) Terms and Conditions

Figure 2 Heatmap Depicting mRNA Expression of Probe Sets of MCF7-ESR1 (Gene Encoding Estrogen Receptor [ER]-α Protein)-siRNA (Small Interfering RNA) Gene Set. Expression Values of 28 of 33 Members of MCF7-ESR1-siRNA Gene Set for Which Data Could Be Generated Across All 1034 Breast Tumors Were Used to Generate a Principal Component (PC). Where Multiple Probe Sets Were Available for Any 1 Gene, These Were Averaged. Tumors (n = 1034) Were Arranged From Low PC Magnitude (Green) to High PC Magnitude (Red; Left to Right). Genes Used to Infer the PC of ER Signaling Were Hierarchically Clustered Using Euclidean Distance and Ward's Method Linkage (Dendrogram Left of Heatmap). Their mRNA Expression Levels Across the Breast Tumors Are Indicated in the Heatmap (High, Red; Low, Green). The Centroid Refers to the Mean Expression Within Each Tumor Abbreviations: ERBB2 = Erb-b2 receptor tyrosine kinase 2/HER2; IHC = immunohistochemistry. Clinical Breast Cancer 2017 17, 139-153DOI: (10.1016/j.clbc.2016.09.001) Copyright © 2016 The Author(s) Terms and Conditions

Figure 3 Comparison of ESR1 (Gene Encoding Estrogen Receptor [ER]-α Protein) mRNA Expression, MCF7-ESR1-siRNA (Small Interfering RNA) First Principal Component (PC) and ER Status. Log2 ESR1 mRNA Levels Were Plotted Against MCF7-ESR1-siRNA PC in Breast Tumors From 5 Selected Microarray Data Sets. (A) GSE36771 (n = 107), (B) GSE1456 (n = 159), (C) GSE3494 (n = 232), (D) GSE6532 (n = 241), (E) GSE36772 (n = 100), (F) All 5 Data Sets (n = 1034). ER Status Determined by Immunohistochemistry Shown as Red for ER− Tumors and Blue for ER+ Tumors Clinical Breast Cancer 2017 17, 139-153DOI: (10.1016/j.clbc.2016.09.001) Copyright © 2016 The Author(s) Terms and Conditions

Figure 4 Comparison of ESR1 (Gene Encoding Estrogen Receptor [ER]-α Protein) mRNA Expression, MCF7-ESR1-siRNA (Small Interfering RNA) Principal Component (PC) and ER Status Across Breast Cancer Subtypes. Log2 ESR1 mRNA Levels Were Plotted Against MCF7-ESR1-siRNA PC in 1034 Breast Tumors Separated by Subtype. (A) Basal-Like (n = 209), (B) Erb-b2 Receptor Tyrosine Kinase 2/HER2-Positive (n = 100), (C) Normal-Like (n = 176), (D) Luminal B (n = 210), (E) Luminal A (n = 291; Tumors That Could Not Be Classified Into a Subtype Were Excluded). ER Status Determined by Immunohistochemistry Shown as Red for ER− Tumors and Blue for ER+ Tumors Clinical Breast Cancer 2017 17, 139-153DOI: (10.1016/j.clbc.2016.09.001) Copyright © 2016 The Author(s) Terms and Conditions

Figure 5 Comparison of ESR1 (Gene Encoding Estrogen Receptor [ER]-α Protein) siRNA (Small Interfering RNA) First Principal Component (PC) with ESR1 and Progesterone Receptor (PGR) mRNA Expression and PGR Status. (A) Log2 ESR1 mRNA Levels Were Plotted Against MCF7-ESR1-siRNA PC in 1034 Breast Tumors. PGR Status Determined by Immunohistochemistry Shown as Red for PGR− Tumors and Blue for PGR+ Tumors. (B) Log2 PGR mRNA Levels Were Plotted Against MCF7-ESR1-siRNA PC in 639 Breast Tumors (Remaining Tumors Had No PGR Status Available). PGR Status Determined by Immunohistochemistry Shown as Red for PGR− Tumors and Blue for PGR+ Tumors Clinical Breast Cancer 2017 17, 139-153DOI: (10.1016/j.clbc.2016.09.001) Copyright © 2016 The Author(s) Terms and Conditions

Figure 6 Association of Gene Sets With Distant Metastasis-Free Survival (DMFS) in Nonadjuvant Treated or Endocrine-Treated Patients. Kaplan-Meier Survival Plots Showing Association of Principal Component of 4 Gene Sets: MCF7-ESR1 (Gene Encoding Estrogen Receptor [ER]-α Protein)-siRNA (Small Interfering RNA), ER+ Versus ER−, Endopredict, PAM50, and Simplified Tamoxifen Predictor and Prognosis of Either Nonadjuvant-Treated or Endocrine-Treated Breast Cancer Patients. Cox Proportional Hazards (CoxPH) and Log-Rank Test (LR) P Values Shown for 4 Gene Sets That Showed the Most Significant Association With DMFS in Patients Receiving Endocrine Therapy. High Indicates Greater Than the Quantile Cutoff; and Low, Less Than the Quantile Cutoff Clinical Breast Cancer 2017 17, 139-153DOI: (10.1016/j.clbc.2016.09.001) Copyright © 2016 The Author(s) Terms and Conditions

Figure 7 Comparison of ESR1 (Gene Encoding Estrogen Receptor [ER]-α Protein) mRNA Expression, MCF7-ESR1-siRNA (Small Interfering RNA) Principal Component (PC) and ER Status. Log2 ESR1 mRNA Levels Were Plotted Against MCF7-ESR1-siRNA PC in Breast Tumors Separated by ER Status (Determined by Immunohistochemistry). (A) ER− Tumors (n = 208) and (B) ER+ Tumors (n = 822). Patients Who Received Endocrine Therapy Shown in Red and Patients Who Did Not Receive Endocrine Therapy in Black Clinical Breast Cancer 2017 17, 139-153DOI: (10.1016/j.clbc.2016.09.001) Copyright © 2016 The Author(s) Terms and Conditions

Supplemental Figure 1 Clinical Breast Cancer 2017 17, 139-153DOI: (10.1016/j.clbc.2016.09.001) Copyright © 2016 The Author(s) Terms and Conditions

Supplemental Figure 2 Clinical Breast Cancer 2017 17, 139-153DOI: (10.1016/j.clbc.2016.09.001) Copyright © 2016 The Author(s) Terms and Conditions

Supplemental Figure 3 Clinical Breast Cancer 2017 17, 139-153DOI: (10.1016/j.clbc.2016.09.001) Copyright © 2016 The Author(s) Terms and Conditions

Supplemental Figure 4 Clinical Breast Cancer 2017 17, 139-153DOI: (10.1016/j.clbc.2016.09.001) Copyright © 2016 The Author(s) Terms and Conditions