title: Mislocalization of p27 to the cytoplasm of breast cancer cells confers resistance to anti-HER2 targeted therapy.
abstract: As a cell cycle inhibitor and tumor suppressor, p27 is frequently misregulated in human cancers. Increased degradation is the most common mechanism of misregulation, however in some cancers, p27 is mislocalized from its cell cycle inhibitory location in the nucleus, to the cytoplasm. In normal cells cytoplasmic p27 has functions that are distinct from its cell cycle-regulatory nuclear functions. Therefore, an important question is whether localization of p27 to the cytoplasm in tumor cells is primarily a mechanism for cancelling its inhibitory effect on cell proliferation, or whether cytoplasmic p27 has more direct oncogenic actions. To study p27 mislocalization in human cancers we screened a panel of common breast cancer cell lines. We observed that p27 accumulated in the cytoplasm exclusively in cell lines that are Her2+. To address the significance of p27 mislocalization in Her2+ breast cancer cells we interrogated the cellular response to the dual-Her2/EGFR kinase inhibitor, lapatinib. Knockdown of p27 using shRNA sensitized Her2+ cells to lapatinib-induced apoptosis. Moreover, expression of a constitutively cytoplasmic form of p27 (p27ΔNLS) reversed the lapatinib-induced apoptosis, suggesting that cytoplasmic p27 contributed to lapatinib resistance in Her2+ breast cancer cells by suppressing apoptosis. Our results suggest that p27 localization may be useful as a predictive biomarker of therapeutic response in patients with Her2+ breast cancers.
authors.affiliation: Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: Claire M
authors.initials: CM
authors.lastname: Faltermeier
authors.affiliation: Biology Department, Whitman College, Walla Walla, Washington, USA.
authors.forename: Lori
authors.initials: L
authors.lastname: Mendelsohn
authors.affiliation: Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: Peggy L
authors.initials: PL
authors.lastname: Porter
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Clurman
authors.affiliation: Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Roberts
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D000077341:Lapatinib; D051379:Mice; D058990:Molecular Targeted Therapy; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D000970:Antineoplastic Agents; D050760:Cyclin-Dependent Kinase Inhibitor p27; D000077341:Lapatinib; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases; C436291:CDKN1B protein, human; C508053:ERBB2 protein, human