title: HP1β is a biomarker for breast cancer prognosis and PARP inhibitor therapy.
abstract: Members of the heterochromatin protein 1 family (HP1α, β and γ) are mostly associated with heterochromatin and play important roles in gene regulation and DNA damage response. Altered expression of individual HP1 subtype has profound impacts on cell proliferation and tumorigenesis. We analyzed the expression profile of HP1 family by data mining using a published microarray data set coupled with retrospective immunohistochemistry analyses of archived breast cancer biospecimens. We found that the patient group overexpressing HP1β mRNA is associated with poorly differentiated breast tumors and with a significantly lower survival rate. Immunohistochemical staining against HP1α, HP1β and HP1γ shows that respective HP1 expression level is frequently altered in breast cancers. 57.4-60.1% of samples examined showed high HP1β expression and 39.9-42.6 % of examined tumors showed no or low expression of each HP1 subtype. Interestingly, comparative analysis on HP1 expression profile and breast cancer markers revealed a positive correlation between the respective expression level of all three HP1 subtypes and Ki-67, a cell proliferation and well-known breast cancer marker. To explore the effect of individual HP1 on PARP inhibitor therapy for breast cancer, MCF7 breast cancer cells and individually HP1-depleted MCF7 cells were treated with PARP inhibitor ABT-888 with or without carboplatin. Notably, HP1β-knockdown cells are hypersensitive to the PARP inhibitor ABT-888 alone and its combination with carboplatin. In summary, while increased HP1β expression is associated with the poor prognosis in breast cancer, compromised HP1β abundance may serve as a useful predictive marker for chemotherapy, including PARP inhibitors against breast cancer.
authors.affiliation: Department of Molecular Pharmacology, Beckman Research Institute, City of Hope, Duarte, California, United States of America.
authors.forename: Young-Ho
authors.initials: YH
authors.lastname: Lee
authors.affiliation: Department of Molecular Pharmacology, Beckman Research Institute, City of Hope, Duarte, California, United States of America.
authors.forename: Xiyong
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Medical Oncology, Second Affiliated Hospital, Zhejiang University, School of Medicine, Hangzhou, China.
authors.forename: Fuming
authors.initials: F
authors.lastname: Qiu
authors.affiliation: Department of Cancer Biology, Beckman Research Institute, City of Hope, Duarte, California, United States of America.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: O'Connor
authors.affiliation: Department of Molecular Pharmacology, Beckman Research Institute, City of Hope, Duarte, California, United States of America.
authors.forename: Yun
authors.initials: Y
authors.lastname: Yen
authors.affiliation: Department of Molecular Pharmacology, Beckman Research Institute, City of Hope, Duarte, California, United States of America.
authors.forename: David K
authors.initials: DK
authors.lastname: Ann
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000175:diagnosis* / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D000090266:Chromobox Protein Homolog 5; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism; D061986:MCF-7 Cells; D008875:Middle Aged; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012189:Retrospective Studies
chemical_list: D014408:Biomarkers, Tumor; C000715593:CBX1 protein, human; C000715594:CBX5 protein, human; D002868:Chromosomal Proteins, Non-Histone; D019394:Ki-67 Antigen; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D012333:RNA, Messenger; D000090266:Chromobox Protein Homolog 5