title: Synergistic antitumor activity of lapatinib and retinoids on a novel subtype of breast cancer with coamplification of ERBB2 and RARA.
abstract: All-trans retinoic acid (ATRA), the only clinically available cyto-differentiating agent, has potential for the therapy/chemoprevention of breast carcinoma. Given the heterogeneous nature of this tumor, a rational use of ATRA and derivatives (retinoids) in the clinic requires the identification of patients that would benefit from retinoid-based protocols. Here, we demonstrate that 23-32% of the human ERBB2(+) breast cancers show coamplification of retinoic acid receptor alpha (RARA), encoding the retinoic acid receptor, RARα. This represents a novel subtype of breast cancer characterized by remarkable sensitivity to ATRA and RARα agonists, regardless of positivity to the estrogen receptor, a known modulator of retinoid sensitivity. In estrogen-receptor-negative cellular models showing coamplification of ERBB2 and RARA, simultaneous targeting of the corresponding gene products with combinations of lapatinib and ATRA causes synergistic growth inhibition, cyto-differentiation and apoptosis. This provides proof-of-principle that coamplification of ERBB2 and RARA can be exploited for the stratified and targeted therapy of a novel subtype of breast cancer patients, with an approach characterized by tumor cell selectivity and low predicted toxicity. The available cellular models were exploited to define the molecular mechanisms underlying the antitumor activity of combinations between lapatinib and ATRA. Global gene expression and functional approaches provide evidence for three components of the antiproliferative/apoptotic responses triggered by lapatinib+ATRA. Induction of the retinoid-dependent RARRES3 protein by ATRA stabilizes the effect of lapatinib inhibiting ERBB2 phosphorylation. Upregulation and activation of the transcription factor FOXO3A integrates ATRA-dependent transcriptional and lapatinib-dependent posttranscriptional signals, controlling the levels of effector proteins like the antiapoptotic factor, BIRC5. Stimulation of the TGFβ pathway by ATRA mediates other components of the apoptotic process set in motion by simultaneous targeting of ERBB2 and RARα.
authors: Laboratory of Molecular Biology, Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy.
authors: G
authors: G
authors: Paroni
authors: M
authors: M
authors: Fratelli
authors: G
authors: G
authors: Gardini
authors: C
authors: C
authors: Bassano
authors: M
authors: M
authors: Flora
authors: A
authors: A
authors: Zanetti
authors: V
authors: V
authors: Guarnaccia
authors: P
authors: P
authors: Ubezio
authors: F
authors: F
authors: Centritto
authors: M
authors: M
authors: Terao
authors: E
authors: E
authors: Garattini
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D004357:Drug Synergism; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005784:Gene Amplification / Q000187:drug effects*; D006801:Humans; D000077341:Lapatinib; D010766:Phosphorylation / Q000187:drug effects; D011799:Quinazolines / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000235:genetics* / Q000378:metabolism; D000072482:Retinoic Acid Receptor alpha; D051900:Smad3 Protein / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D059467:Transcriptome / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D000077341:Lapatinib; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; D014212:Tretinoin; C499517:FOXO3 protein, human; C000607071:RARA protein, human