title: PPM1H is a p27 phosphatase implicated in trastuzumab resistance.
abstract: The HER2 oncogene is overexpressed or amplified in 20% of breast cancers. HER2-positive cancer historically portends a poor prognosis, but the HER2-targeted therapy trastuzumab mitigates this otherwise ominous distinction. Nevertheless, some patients suffer disease recurrence despite trastuzumab, and metastatic disease remains largely incurable due to innate and acquired resistance. Thus, understanding trastuzumab resistance remains an unmet medical need. Through RNA interference screening, we discovered that knockdown of the serine/threonine phosphatase PPM1H confers trastuzumab resistance via reduction in protein levels of the tumor suppressor p27. PPM1H dephosphorylates p27 at threonine 187, thus removing a signal for proteasomal degradation. We further determined that patients whose tumors express low levels of PPM1H trend towards worse clinical outcome on trastuzumab. Identifying PPM1H as a novel p27 phosphatase reveals new insight into how cancer cells destabilize a well-recognized tumor suppressor. Furthermore, low PPM1H expression may identify a subset of HER2-positive tumors that are harder to treat.
authors.affiliation: Genentech Research and Early Development, South San Francisco, California 94080, USA.
authors.forename: Si Tuen
authors.initials: ST
authors.lastname: Lee-Hoeflich
authors.forename: Thinh Q
authors.initials: TQ
authors.lastname: Pham
authors.forename: Don
authors.initials: D
authors.lastname: Dowbenko
authors.forename: Xander
authors.initials: X
authors.lastname: Munroe
authors.forename: James
authors.initials: J
authors.lastname: Lee
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Wei
authors.initials: W
authors.lastname: Zhou
authors.forename: Peter M
authors.initials: PM
authors.lastname: Haverty
authors.forename: Kanan
authors.initials: K
authors.lastname: Pujara
authors.forename: Jeremy
authors.initials: J
authors.lastname: Stinson
authors.forename: Sara M
authors.initials: SM
authors.lastname: Chan
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Eastham-Anderson
authors.forename: Ajay
authors.initials: A
authors.lastname: Pandita
authors.forename: Somasekar
authors.initials: S
authors.lastname: Seshagiri
authors.forename: Klaus P
authors.initials: KP
authors.lastname: Hoeflich
authors.forename: Gulisa
authors.initials: G
authors.lastname: Turashvili
authors.forename: Karen A
authors.initials: KA
authors.lastname: Gelmon
authors.forename: Samuel A
authors.initials: SA
authors.lastname: Aparicio
authors.forename: David P
authors.initials: DP
authors.lastname: Davis
authors.forename: Mark X
authors.initials: MX
authors.lastname: Sliwkowski
authors.forename: Howard M
authors.initials: HM
authors.lastname: Stern
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics*; D019008:Drug Resistance, Neoplasm; D005260:Female; D018734:Genes, erbB-2; D057809:HEK293 Cells; D006801:Humans; D010749:Phosphoprotein Phosphatases / Q000235:genetics* / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D000068878:Trastuzumab; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D050760:Cyclin-Dependent Kinase Inhibitor p27; D010749:Phosphoprotein Phosphatases; D046988:Proteasome Endopeptidase Complex; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; D025521:Tumor Suppressor Proteins; C508053:ERBB2 protein, human; C521058:PPM1H protein, human