title: The HER2 amplicon includes several genes required for the growth and survival of HER2 positive breast cancer cells.
abstract: About 20% of breast cancers are characterized by amplification and overexpression of the HER2 oncogene. Although significant progress has been achieved for treating such patients with HER2 inhibitor trastuzumab, more than half of the patients respond poorly or become resistant to the treatment. Since the HER2 amplicon at 17q12 contains multiple genes, we have systematically explored the role of the HER2 co-amplified genes in breast cancer cell growth and their relation to trastuzumab resistance. We integrated aCGH data of the HER2 amplicon from 71 HER2 positive breast tumors and 10 cell lines with systematic functional RNA interference analysis of 23 core amplicon genes with several phenotypic endpoints in a panel of trastuzumab responding and non-responding HER2 positive breast cancer cells. Silencing of HER2 caused a greater growth arrest and apoptosis in the responding compared to the non-responding cell lines, indicating that the resistant cells are inherently less dependent on the HER2 pathway. Several other genes in the amplicon also showed a more pronounced effect when silenced; indicating that expression of HER2 co-amplified genes may be needed to sustain the growth of breast cancer cells. Importantly, co-silencing of STARD3, GRB7, PSMD3 and PERLD1 together with HER2 led to an additive inhibition of cell viability as well as induced apoptosis. These studies indicate that breast cancer cells may become addicted to the amplification of several genes that reside in the HER2 amplicon. The simultaneous targeting of these genes may increase the efficacy of the anti-HER2 therapies and possibly also counteract trastuzumab resistance. The observed additive effects seem to culminate to both apoptosis and cell proliferation pathways indicating that these pathways may be interesting targets for combinatorial treatment of HER2+ breast cancers.
authors.affiliation: Department of Genetics, Institute for Cancer Research, Division of Surgery and Cancer, Oslo University Hospital, Radiumhospitalet, 0310 Oslo, Norway. kristine.kleivi@rr-research.no
authors.forename: Kristine Kleivi
authors.initials: KK
authors.lastname: Sahlberg
authors.forename: Vesa
authors.initials: V
authors.lastname: Hongisto
authors.forename: Henrik
authors.initials: H
authors.lastname: Edgren
authors.forename: Rami
authors.initials: R
authors.lastname: Mäkelä
authors.forename: Kirsi
authors.initials: K
authors.lastname: Hellström
authors.forename: Eldri U
authors.initials: EU
authors.lastname: Due
authors.forename: Hans Kristian
authors.initials: HK
authors.lastname: Moen Vollan
authors.forename: Niko
authors.initials: N
authors.lastname: Sahlberg
authors.forename: Maija
authors.initials: M
authors.lastname: Wolf
authors.forename: Anne-Lise
authors.initials: AL
authors.lastname: Børresen-Dale
authors.forename: Merja
authors.initials: M
authors.lastname: Perälä
authors.forename: Olli
authors.initials: O
authors.lastname: Kallioniemi
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001940:Breast / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D005260:Female; D005784:Gene Amplification; D006801:Humans; D034622:RNA Interference; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D000068878:Trastuzumab
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab