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Synergistic Antitumor Activity of Lapatinib and Retinoids on a Novel Subtype of Breast Cancer with Coamplification of ERBB2 and RARA

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Synergistic Antitumor Activity of Lapatinib and Retinoids on a Novel Subtype of Breast Cancer with Coamplification of ERBB2 and RARA Oncogene (2012) 31, 3431–3443 & 2012 Macmillan Publishers Limited All rights reserved 0950-9232/12 www.nature.com/onc ORIGINAL ARTICLE Synergistic antitumor activity of lapatinib and retinoids on a novel subtype of breast cancer with coamplification of ERBB2 and RARA G Paroni1, M Fratelli1, G Gardini2, C Bassano2, M Flora2, A Zanetti1, V Guarnaccia1, P Ubezio3, F Centritto1, M Terao1 and E Garattini1 1Laboratory of Molecular Biology, Istituto di Ricerche Farmacologiche ‘Mario Negri’, Milano, Italy; 2Anatomic Pathology Unit, IRCCS Ospedale Santa Maria Nuova, Reggio Emilia, Italy and 3Department of Oncology, Istituto di Ricerche Farmacologiche ‘Mario Negri’, Milano, Italy All-trans retinoic acid (ATRA), the only clinically Oncogene (2012) 31, 3431–3443; doi:10.1038/onc.2011.506; available cyto-differentiating agent, has potential for the published online 7 November 2011 therapy/chemoprevention of breast carcinoma. Given the heterogeneous nature of this tumor, a rational use of Keywords: targeted therapy; retinoic acid; differentia- ATRA and derivatives (retinoids) in the clinic requires the tion; apoptosis; HER2/neu; lapatinib identification of patients that would benefit from retinoid- based protocols. Here, we demonstrate that 23–32% of the human ERBB2 þ breast cancers show coamplification of retinoic acid receptor alpha (RARA), encoding the Introduction retinoic acid receptor, RARa. This represents a novel subtype of breast cancer characterized by remarkable Breast carcinoma is classified according to the presence/ sensitivity to ATRA and RARa agonists, regardless of absence of estrogen receptor (ER), progesterone recep- positivity to the estrogen receptor, a known modulator of tor and ERBB2 (also known as HER2/Neu) (Rubin and retinoid sensitivity. In estrogen-receptor-negative cellular Yarden, 2001). ERBB2 þ patients used to have a poor models showing coamplification of ERBB2 and RARA, prognosis until the advent of targeted therapy (Baselga, simultaneous targeting of the corresponding gene products 2006; Baselga and Swain, 2009), which relies on with combinations of lapatinib and ATRA causes trastuzumab (Esteva et al.; Mariani et al., 2009) and synergistic growth inhibition, cyto-differentiation and lapatinib (Moreira and Kaklamani, 2010). In spite of apoptosis. This provides proof-of-principle that coampli- this progress, not all patients in this group benefit from fication of ERBB2 and RARA can be exploited for the trastuzumab-based therapies (Hudis, 2007; Esteva et al., stratified and targeted therapy of a novel subtype of breast 2010). In addition, a subset of patients progress after an cancer patients, with an approach characterized by tumor initial response. Innate and acquired resistance to HER2 cell selectivity and low predicted toxicity. The available targeting calls for the development of new and rational cellular models were exploited to define the molecular therapeutic approaches. This is likely to entail the mechanisms underlying the antitumor activity of combina- development of combination strategies involving simul- tions between lapatinib and ATRA. Global gene expres- taneous targeting of determinants crucial for the growth sion and functional approaches provide evidence for three and progression of the tumor (Abramson and Arteaga, components of the antiproliferative/apoptotic responses 2011). triggered by lapatinib þ ATRA. Induction of the retinoid- All-trans retinoic acid (ATRA), the only clinically dependent RARRES3 protein by ATRA stabilizes the useful differentiating agent (Garattini et al., 2007) has effect of lapatinib inhibiting ERBB2 phosphorylation. potential for the therapy/chemoprevention of breast Upregulation and activation of the transcription factor carcinoma (Decensi et al., 2000; Puntoni and Decensi, FOXO3A integrates ATRA-dependent transcriptional 2009). Given the heterogeneous nature of this tumor, a and lapatinib-dependent posttranscriptional signals, con- rational use of ATRA and derivatives (retinoids) in the trolling the levels of effector proteins like the antiapopto- clinic requires the identification of patients that would tic factor, BIRC5. Stimulation of the TGFb pathway by benefit from retinoid-based protocols. ATRA mediates other components of the apoptotic The antitumor activity of retinoids is mediated by process set in motion by simultaneous targeting of ERBB2 specific nuclear receptors (RARa, b, g and RXRa, b, g, and RARa. which are ligand-dependent transcription factors (Kast- ner et al., 1995; Chambon, 1996). In breast cancer cells, RARa expression is controlled by estrogens, and high Correspondence: Dr E Garattini, Laboratory of Molecular Biology, levels of the protein are observed in estrogen-receptor- Istituto di Ricerche Farmacologiche ‘Mario Negri’, via La Masa 19, positive (ER þ ) tumors (Sun et al., 1998). RARa 20156 Milano, Italy. expression determines sensitivity of ER þ and refractori- E-mail: [email protected] À Received 13 August 2011; revised and accepted 1 October 2011; ness of ER breast cancer cells to retinoids (Roman published online 7 November 2011 et al., 1993; Sheikh et al., 1993; Fitzgerald et al., 1997). Antitumor activity of retinoids and lapatinib GParoniet al 3432 Retinoic acid receptor alpha (RARA), the gene causing 50% maximal growth inhibition) (Figure 1c; encoding RARa, maps close (0.65 Mb) to the ERBB2 Supplementary Figure S1). With the exception of BT474, locus, which is generally amplified in ERBB2 þ breast all ER þ cells responded to ATRA in the micromolar carcinoma. Here, we establish that a proportion of range. ERÀ/ERBB2 þ /RARAÀ cells were resistant, ERBB2 þ tumors are characterized by an amplicon whereas the ERÀ/ERBB2 þ /RARA þ cells, SKBR3 and encompassing RARA, which confers retinoid sensitivity AU565, were more sensitive to ATRA (nanomolar upon the ERÀ neoplastic cell. This genetic makeup was range) than the ER þ counterparts. All the cell lines, exploited for concomitant targeting of ERBB2 and regardless of the ER status, synthesized detectable levels RARa, obtaining synergistic antitumor effects. The of RARg and RXRa (Figure 1c), but showed no underlying molecular mechanisms were studied. detectable expression of RARb. ATRA sensitivity was directly correlated to RARa levels in ERÀ cells. The two ERÀ/luminal lines, SKBR3 (ERBB2 þ / Results RARA þ ) and MDA-MB-453 (ERBB2 þ /RARAÀ), were used for subsequent studies (Supplementary Figure A subgroup of breast carcinomas shows ERBB2/RARA S2a). ATRA-dependent growth inhibition was accom- coamplification panied by differentiation of SKBR3 but not MDA-MB- We defined that a proportion of ERBB2 þ breast 453 cells. This effect was detectable at 0.1 mM and carcinomas was characterized by RARA amplification maximal at 1 mM ATRA. Differentiation included (ERBB2 þ /RARA þ ) by real-time quantitative PCR accumulation of oil-red droplets (lactogenesis) (Supple- assays (Q-PCR). Histological sections of 74 tumors mentary Figure S2b) and appearance of adherens positive for ERBB2 by fluorescence in situ hybridiza- junctions containing b-catenin, p120 and VE-cadherin tion (FISH) and 2 ERBB2À controls were analyzed (Supplementary Figure S2c; Dusek and Attardi, 2011). (Figures 1a and b, Supplementary Table S1). Most cases This was accompanied by the induction of the three (76%) proved positive for ERBB2 amplification by Q– proteins (see also Figure 2d) and restructuring of the PCR, when a conservative threshold value was applied. actin cytoskeleton. Growth inhibition and differentia- Coamplification of the RARA locus was found in 23% tion were directly correlated to ligand-dependent activa- of the patients by Q–PCR and 32% by FISH. If samples tion of retinoid receptors, as treatment with ATRA were stratified for ER, no difference in the proportion of caused sustained activation of the transfected retinoid ERBB2 þ /RARA þ patients was evident. reporter, RARE-tk-Luc (Gianni et al., 2009), only in SKBR3 cells (Supplementary Figure S2d). To verify the role of RARA amplification, we compared the activities ERÀ cell lines recapitulating ERBB2 and RARA et al. coamplification are sensitive to retinoids of ATRA (pan-RAR agonist) (Garattini , 2004), the RARa agonist, AM580 (Gianni et al., 1996a), and Five ERÀ and five ER þ breast carcinoma cell lines over- the RARg agonist, CD437 (Gianni et al., 1993), in expressing the ERBB2 protein and two negative controls SKBR3 and MDA-MB-453 cells. AM580 and ATRA (MDA-MB-231 and MCF-7) were evaluated for RARA arrested the growth and induced differentiation of amplification by Q–PCR (Figure 1c). Except for ZR75.1, SKBR3 cells, whereas CD437 was inactive (Supplemen- all ERÀ and ER þ cells with ERBB2 overexpression tary Figures S2a and e). In SKBR3 cells, this is showed amplification of the corresponding gene. The correlated with the activation of transfected RARE-tk- ER þ line, UACC812, and the ERÀ lines, SKBR3 and Luc by the two agonists (Supplementary Figure S2f). AU565, showed ERBB2/RARA coamplification. All ER þ cells contained more RARa than their ERÀ counterparts, and UACC812 synthesized the largest Lapatinib potentiates the activity of ATRA in ERÀ/ amounts of the receptor. In the context of ER- ERBB2 þ /RARA þ cells negativity, the two ERBB2 þ /RARA þ lines, SKBR3 We evaluated whether simultaneous targeting of RARa and AU565, showed significant expression of RARa, and ERBB2 represented a potential therapeutic ap- whereas the ERBB2 þ /RARAÀ lines presented barely proach for ERÀ/ERBB2 þ /RARA þ breast cancer. Lapa- detectable levels of the protein (Figure 1c). tinib, rather than
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