title: Genetic variations in the Hippo signaling pathway and breast cancer risk in African American women in the AMBER Consortium.
abstract: The Hippo signaling pathway regulates cellular proliferation and survival, thus exerting profound effects on normal cell fate and tumorigenesis. Dysfunction of the Hippo pathway components has been linked with breast cancer stem cell regulation, as well as breast tumor progression and metastasis. TAZ, a key component of the Hippo pathway, is highly expressed in triple negative breast cancer; however, the associations of genetic variations in this important pathway with breast cancer risk remain largely unexplored. Here, we analyzed 8309 germline variants in 15 genes from the Hippo pathway with a total of 3663 cases and 4687 controls from the African American Breast Cancer Epidemiology and Risk Consortium. Odds ratios (ORs) were estimated using logistic regression for overall breast cancer, by estrogen receptor (ER) status (1983 ER positive and 1098 ER negative), and for case-only analyses by ER status. The Hippo signaling pathway was significantly associated with ER-negative breast cancer (pathway level P = 0.02). Gene-based analyses revealed that CDH1 was responsible for the pathway association (P < 0.01), with rs4783673 in CDH1 statistically significant after gene-level adjustment for multiple comparisons (P = 9.2×10(-5), corrected P = 0.02). rs142697907 in PTPN14 was associated with ER-positive breast cancer and rs2456773 in CDK1 with ER-negativity in case-only analysis after gene-level correction for multiple comparisons (corrected P < 0.05). In conclusion, common genetic variations in the Hippo signaling pathway may contribute to both ER-negative and ER+ breast cancer risk in AA women.
authors.forename: Jianmin
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
authors.forename: Song
authors.initials: S
authors.lastname: Yao
authors.affiliation: Department of Biostatistics and Bioinformatics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Hu
authors.affiliation: Department of Biostatistics and Bioinformatics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
authors.forename: Qianqian
authors.initials: Q
authors.lastname: Zhu
authors.affiliation: Department of Biostatistics and Bioinformatics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
authors.forename: Song
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA.
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Lunetta
authors.affiliation: Slone Epidemiology Center at Boston University, Boston, MA 02215, USA.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Haddad
authors.forename: Nuo
authors.initials: N
authors.lastname: Yang
authors.forename: He
authors.initials: H
authors.lastname: Shen
authors.affiliation: Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
authors.forename: Chi-Chen
authors.initials: CC
authors.lastname: Hong
authors.affiliation: Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
authors.forename: Lara
authors.initials: L
authors.lastname: Sucheston-Campbell
authors.affiliation: Slone Epidemiology Center at Boston University, Boston, MA 02215, USA.
authors.forename: Edward A
authors.initials: EA
authors.lastname: Ruiz-Narvaez
authors.affiliation: Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Jeannette T
authors.initials: JT
authors.lastname: Bensen
authors.affiliation: Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Troester
authors.affiliation: Cancer Prevention and Control Program, Rutgers Cancer Institute of New Jersey, The State University of New Jersey, New Brunswick, NJ 08901, USA, and.
authors.forename: Elisa V
authors.initials: EV
authors.lastname: Bandera
authors.affiliation: Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA.
authors.forename: Lynn
authors.initials: L
authors.lastname: Rosenberg
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA 90089, USA.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Haiman
authors.affiliation: Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Andrew F
authors.initials: AF
authors.lastname: Olshan
authors.affiliation: Slone Epidemiology Center at Boston University, Boston, MA 02215, USA.
authors.forename: Julie R
authors.initials: JR
authors.lastname: Palmer
authors.affiliation: Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
authors.forename: Christine B
authors.initials: CB
authors.lastname: Ambrosone
mesh_terms: D015703:Antigens, CD; D016203:CDC2 Protein Kinase / Q000235:genetics*; D015820:Cadherins / Q000235:genetics*; D047628:Estrogen Receptor alpha / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D000090683:Hippo Signaling Pathway; D006801:Humans; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000235:genetics; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000235:genetics*; D012307:Risk Factors; D015398:Signal Transduction; D064726:Triple Negative Breast Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D009363:Neoplasm Proteins; D017346:Protein Serine-Threonine Kinases; D016203:CDC2 Protein Kinase; C093261:PTPN14 protein, human; D054558:Protein Tyrosine Phosphatases, Non-Receptor