title: HER2 Signaling Drives DNA Anabolism and Proliferation through SRC-3 Phosphorylation and E2F1-Regulated Genes.
abstract: Approximately 20% of early-stage breast cancers display amplification or overexpression of the ErbB2/HER2 oncogene, conferring poor prognosis and resistance to endocrine therapy. Targeting HER2(+) tumors with trastuzumab or the receptor tyrosine kinase (RTK) inhibitor lapatinib significantly improves survival, yet tumor resistance and progression of metastatic disease still develop over time. Although the mechanisms of cytosolic HER2 signaling are well studied, nuclear signaling components and gene regulatory networks that bestow therapeutic resistance and limitless proliferative potential are incompletely understood. Here, we use biochemical and bioinformatic approaches to identify effectors and targets of HER2 transcriptional signaling in human breast cancer. Phosphorylation and activity of the Steroid Receptor Coactivator-3 (SRC-3) is reduced upon HER2 inhibition, and recruitment of SRC-3 to regulatory elements of endogenous genes is impaired. Transcripts regulated by HER2 signaling are highly enriched with E2F1 binding sites and define a gene signature associated with proliferative breast tumor subtypes, cell-cycle progression, and DNA replication. We show that HER2 signaling promotes breast cancer cell proliferation through regulation of E2F1-driven DNA metabolism and replication genes together with phosphorylation and activity of the transcriptional coactivator SRC-3. Furthermore, our analyses identified a cyclin-dependent kinase (CDK) signaling node that, when targeted using the CDK4/6 inhibitor palbociclib, defines overlap and divergence of adjuvant pharmacologic targeting. Importantly, lapatinib and palbociclib strictly block de novo synthesis of DNA, mostly through disruption of E2F1 and its target genes. These results have implications for rational discovery of pharmacologic combinations in preclinical models of adjuvant treatment and therapeutic resistance.
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
authors.forename: Bryan C
authors.initials: BC
authors.lastname: Nikolai
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
authors.forename: Rainer B
authors.initials: RB
authors.lastname: Lanz
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
authors.forename: Brian
authors.initials: B
authors.lastname: York
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
authors.forename: Subhamoy
authors.initials: S
authors.lastname: Dasgupta
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas. Department of Medicine, Baylor College of Medicine, Houston, Texas. Center for Drug Discovery, Baylor College of Medicine, Houston, Texas.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Mitsiades
authors.affiliation: Department of Medicine, Baylor College of Medicine, Houston, Texas. Dan L. Duncan Cancer Center Division of Biostatistics, Baylor College of Medicine, Houston, Texas.
authors.forename: Chad J
authors.initials: CJ
authors.lastname: Creighton
authors.affiliation: Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas.
authors.forename: Anna
authors.initials: A
authors.lastname: Tsimelzon
authors.affiliation: Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas.
authors.forename: Susan G
authors.initials: SG
authors.lastname: Hilsenbeck
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
authors.forename: David M
authors.initials: DM
authors.lastname: Lonard
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
authors.forename: Carolyn L
authors.initials: CL
authors.lastname: Smith
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas. berto@bcm.edu.
authors.forename: Bert W
authors.initials: BW
authors.lastname: O'Malley
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D001665:Binding Sites / Q000187:drug effects / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics*; D018844:Cyclin-Dependent Kinases / Q000235:genetics; D004247:DNA / Q000235:genetics*; D004261:DNA Replication / Q000187:drug effects / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D050687:E2F1 Transcription Factor / Q000235:genetics*; D005260:Female; D006801:Humans; D056921:Nuclear Receptor Coactivator 3 / Q000235:genetics*; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D018844:Cyclin-Dependent Kinases; D004247:DNA; D050687:E2F1 Transcription Factor; D056921:Nuclear Receptor Coactivator 3; D018719:Erb-b2 Receptor Tyrosine Kinases; C493753:E2F1 protein, human; C538866:NCOA3 protein, human; C508053:ERBB2 protein, human
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