title: TMSB4Y is a candidate tumor suppressor on the Y chromosome and is deleted in male breast cancer.
abstract: Male breast cancer comprises less than 1% of breast cancer diagnoses. Although estrogen exposure has been causally linked to the development of female breast cancers, the etiology of male breast cancer is unclear. Here, we show via fluorescence in situ hybridization (FISH) and droplet digital PCR (ddPCR) that the Y chromosome was clonally lost at a frequency of ~16% (5/31) in two independent cohorts of male breast cancer patients. We also show somatic loss of the Y chromosome gene TMSB4Y in a male breast tumor, confirming prior reports of loss at this locus in male breast cancers. To further understand the function of TMSB4Y, we created inducible cell lines of TMSB4Y in the female human breast epithelial cell line MCF-10A. Expression of TMSB4Y resulted in aberrant cellular morphology and reduced cell proliferation, with a corresponding reduction in the fraction of metaphase cells. We further show that TMSB4Y interacts directly with β-actin, the main component of the actin cytoskeleton and a cell cycle modulator. Taken together, our results suggest that clonal loss of the Y chromosome may contribute to male breast carcinogenesis, and that the TMSB4Y gene has tumor suppressor properties.
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Hong Yuen
authors.initials: HY
authors.lastname: Wong
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Grace M
authors.initials: GM
authors.lastname: Wang
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Croessmann
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Zabransky
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: David
authors.initials: D
authors.lastname: Chu
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Garay
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.|Present address: Oncology iMED, AstraZeneca, Waltham, MA, USA.
authors.forename: Justin
authors.initials: J
authors.lastname: Cidado
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Rory L
authors.initials: RL
authors.lastname: Cochran
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Julia A
authors.initials: JA
authors.lastname: Beaver
authors.affiliation: Veterans Affairs Medical Center, Washington, DC, USA.|The Georgetown University, Washington, DC, USA.|George Washington University School of Medicine, Washington, DC, USA.
authors.forename: Anita
authors.initials: A
authors.lastname: Aggarwal
authors.affiliation: Veterans Affairs Medical Center, Washington, DC, USA.|George Washington University School of Medicine, Washington, DC, USA.
authors.forename: Min-Ling
authors.initials: ML
authors.lastname: Liu
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Pedram
authors.initials: P
authors.lastname: Argani
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Meeker
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Paula J
authors.initials: PJ
authors.lastname: Hurley
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Josh
authors.initials: J
authors.lastname: Lauring
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.|The Whiting School of Engineering, Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Ben Ho
authors.initials: BH
authors.lastname: Park
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D018567:Breast Neoplasms, Male / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D049109:Cell Proliferation; D048430:Cell Shape; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D041322:Chromosomes, Human, Y; D005260:Female; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D042361:Mammary Glands, Human / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D016133:Polymerase Chain Reaction; D013947:Thymosin / Q000235:genetics* / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism; D000099201:Thymosin beta(4)
chemical_list: D000199:Actins; D013947:Thymosin; D025521:Tumor Suppressor Proteins; D000099201:Thymosin beta(4)
keywords: TMSB4Y; Y chromosome; cancer genetics; male breast cancer; tumor suppressor