The Widening Sphere of Influence of HOXB7 in Solid Tumors

Published OnlineFirst April 20, 2016; DOI: 10.1158/0008-5472.CAN-15-3444

Cancer Review Research

The Widening Sphere of Inﬂuence of HOXB7 in Solid Tumors Maria Cristina Errico1, Kideok Jin2, Saraswati Sukumar2, and Alessandra Care1

Abstract

Strong lines of evidence have established a critical role for the poor outcome of cancer patients. Speciﬁc inhibition of HOXB7 is homeodomain protein HOXB7 in cancer. Speciﬁcally, molecular particularly relevant in cancers still lacking effective therapies, and cellular studies have demonstrated that HOXB7 is a master such as tamoxifen-resistant breast cancer and melanoma. Mech- regulatory gene, capable of orchestrating a variety of target mole- anistic studies are providing additional targets of therapy, and cules, resulting in the activation of several oncogenic pathways. biomarker studies are further establishing its importance in early HOXB7 overexpression correlates with clinical progression and diagnosis and prognosis. Cancer Res; 76(10); 2857–62. 2016 AACR.

Introduction In addition, a number of epigenetic regulatory mechanisms have been reported for HOXB7, including changes in methylation HOX genes encode a family of transcription factors that deter- status and histone posttranslational modifications, microRNA mines cellular identity during development (1). Although these (miRNA)-based targeting and long noncoding-RNAs (lncRNA) proteins are generally silenced in adult cells, a substantial number modulation (6–9). of studies have reported their reexpression in a wide variety of neoplasia (2). The role of HOXB7 in cancer is not surprising given its involvement in all the major cellular processes where, through A Functional Role for Overexpressed overexpression or amplification, it appears to act as a master HOXB7 in Solid Tumors regulatory gene capable of orchestrating a wide variety of target molecules in oncogenic hierarchy (Fig. 1; ref. 2). Predictably, A number of studies on HOXB7 have strongly established its HOXB7 expression has been reported to be correlated with clinical critical role in different solid tumors (Fig. 2). Here, we highlight progression and poor outcome of cancer patients, thus suggesting the growing body of knowledge on HOXB7 in a number of human that this protein is a potential prognostic factor and therapeutic cancers, including breast cancer, melanoma, colorectal cancer, target (3). pancreatic ductal adenocarcinoma, oral squamous cell carcino- Although HOX gene clusters are a paradigm of genetic redun- mas, epithelial ovarian carcinoma, and lung cancer. dancy resulting from genome duplications, HOX proteins display a high level of regulatory specificity and stability of DNA-binding Breast cancer through cooperation with cofactors and other transcription fac- The study of cancer gene expression patterns has led to the tors. These cofactors are members of the three amino acid loop identification of genes whose dysregulation, including recurrent extension (TALE) family that includes PBX (PBX1, 2, 3, and 4), DNA amplification, may contribute to tumorigenesis and tumor MEIS (MEIS1, 2, and 3), and PREP (PREP1 and 2; ref. 4). An progression. Hyman and colleagues performed high-resolution example of such cooperation is the HOXB7/PBX2-dependent CGH analysis in breast tumors with accompanying cDNA micro- upregulation of miR-221 and miR-222 in human melanoma cell array data and showed that about half of the highly amplified lines, where the requirement of PBX cofactors for HOXB7-depen- genes were also overexpressed (10). Interestingly, they detected dent tumorigenesis was highlighted (5). HOXB7 amplification in 10% of 363 primary breast cancers and found a direct correlation between HOXB7 amplification and poor prognosis. In a different study, Sukumar's group reported a significantly higher percentage of breast tumors that displayed 1Department of Hematology, Oncology and Molecular Medicine, Isti- 2 HOXB7 overexpression (60%), indicating that mechanisms other tuto Superiore di Sanita, Rome, Italy. Department of Oncology, Johns fi HOXB7 Hopkins University School of Medicine, Baltimore, Maryland. than genomic ampli cation might be involved in deregulation (11). In addition, this group showed the ability of HOXB7 Corresponding Authors: Saraswati Sukumar, Breast and Ovarian Cancer Pro- gram, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Univer- to drive epithelial cells toward a more mesenchymal phenotype sity School of Medicine, 1650 Orleans Street, CRB 1, Room 143, Baltimore, MD (EMT) through the upregulation of bFGF and the activation of the 21231-1000. Phone: 410-614-2479; Fax: 410-614-4073; E-mail: [email protected]; MAPK pathway (11). These studies supported the previously and Alessandra Care, Istituto Superiore di Sanita, Department of Hematology, reported identification of bFGF as a direct target of HOXB7, both Oncology and Molecular Medicine, Molecular Oncology Section, Viale Regina in melanoma (12) and in the SKBR3 breast adenocarcinoma cell Elena 299-00161, Rome, Italy. Phone: 390649902411; Fax: 390649387087; line, where enforced expression of HOXB7 resulted in bFGF E-mail: [email protected] transcription and induction of a more aggressive phenotype doi: 10.1158/0008-5472.CAN-15-3444 (13, 14). The high levels of expression of HOXB7 in lymph-node 2016 American Association for Cancer Research. metastasis-positive ductal carcinomas strengthened its correlation

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Apoptosis Angiogenesis Proliferation

Angiopoietin-TIE2 pathway

VEGF pathway p16INK4a-RB pathway HOXB7/PBX2-miR221 & 222-cfos pathway IL8 pathway HOXB7/PBX2-miR221 & 222-p27 pathway p53 pathway

bFGF-ETS1-BMP4 pathway FGFR and MAPK EMT HOXB7 Migration pathway p16INK4a-RB pathway

Nonhomologous end- joining (NHEJ) pathway HOXB7-EGFR-MAPK- pER pathway TGFβ pathway PARP1 MYC-HOXB7-HER2 GBP1 pathway

DNA repair Invasiveness Drug resistance

Figure 1. Involvement of HOXB7 in known pathways critical to initiation and progression of solid cancers.

with the malignant behavior of breast cancer cells (15). Interest- to be mediated through its interaction with Ku70, Ku80, and ingly, by using a double transgenic MMTV-HoxB7/HER2 mouse DNA-PKcs, factors involved in the nonhomologous end-joining model of breast carcinogenesis, Chen and colleagues discovered pathway. Further, this effect was reversed by suppressing HOXB7 dual roles for HoxB7, as HoxB7 inhibited the initial development (18). The authors suggested that enhanced resistance to IR of mammary tumors but later promoted faster tumor growth and observed in HOXB7-expressing cells could allow them to accu- dissemination to the lungs (16). Although previous reports mulate mutations that initiate tumorigenesis, thus reconciling showed that HOXB7 is capable of inducing angiogenesis in HOXB7's role in DNA repair with its involvement in neoplastic human breast cancer cell line xenografts by upregulating proan- transformation (18). giogenic factors (VEGF, Ang2, GROa, and IL8; refs. 13, 14), no Looking for a comprehensive profile of genes transcriptionally dramatic effects on angiogenesis were observed in the transgenic regulated by HOXB7, a recent study by Jin and colleagues used mice, likely due to innate differences in the immune-deficient bioinformatic analysis of combined ChIP-seq and gene expres- transplanted versus immune-competent autochthonous tumor sion datasets (ChIP-PED) to identify a correlation between model systems (16). Recently, HoxB7-dependent activation of the HOXB7-binding sites and ER target gene expression in the breast TGFb signaling pathway was also reported in the same model cancer cell line, MCF7 (19). Heinonen and colleagues found system. Specifically, HOXB7 overexpression induced TGFb2, lead- more than 1,500 chromatin HOXB7-binding sites in BT474 breast ing to increased cell motility and invasiveness as well as recruit- cancer cells using ChIP-seq (20). The genes located near the ment and activation of macrophages (17). binding sites were potential targets of HOXB7, although, contrary HOXB7 has also been reported to play a crucial role in DNA to prediction, the authors demonstrated that HOXB7 preferen- repair. Rubin and colleagues demonstrated that HOXB7-expres- tially bound to distal enhancer regions rather than to the pro- sing breast cancer cell lines exhibited both a transformed pheno- moters of its target genes (20). However, because HOXB7 up- or type and an enhanced survival after irradiation (IR; ref. 18). Using downregulation per se might be insufficient to produce all the a combination of in vitro and in vivo approaches, HOXB7's ability revealed effects, further studies are required to decipher the to stimulate DNA double-strand breaks (DSB) repair was found molecular and biological effects of HOXB7-mediated regulation.

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HOXB7 Action in Solid Tumors

A B

SPARC HOXB4 HOXA5 mir-196a-1 HOXO6 SLC7A5 TPM4 mir-196a-2 MYB TYRP1 SDHAF2 HOXB5 SLC3A MLH1 RTKN EGF CYP2D6 HOXC5 ITGAV DRG1 MAPT PML SOD2 CLDN1 HOXB5 HOXA1 BMP4 ZBTB16 CLDN4 BTG2 ETS1 VIM EDF1 HOXC11 MMP9 ERBB3 HOXB2 PGR HOXD12 FOS CXCL10 ACTB HOXB3 IFAP2A FGF2 HOXD3 RHOA ERBB2 ANGPT2 CLDN7 TBP ESR1 TP53 XRCO6 PRKDC TIE1 SPTA1 HOXA16 EGFR AR IL8 HOXB7 CXCL2 FGFR2 MAPK1 HOXB7 CDK2 VEGFA PBX1 FGF7 SPNS1 FOS GAPDH FAM89B FGF2 CASP3 SMAD3 PROM1 AREG ACTB MAPK3 CDH1 MMP2 ANGPT PARP1 TIE1 PBX1 JUN CDKN2A PBX2 PKNOX2 XRCC5 GAPDH ILB CREBBP CDKN2A MMP2 TGFB2 PKNOX1 TGFA ANGPT ANGPT2 NR3C1 HPSE MK167 BRAF FGFR2 mir-221 MCAM PKNOX1 MMP9 HPSE VEGFA CD34 PKNOX2 mir-222 FN1 CD34 PBX2 PTEN

Figure 2. Network of proteins and miRNAs (nodes) linking HOXB7 described in breast cancer (A) and melanoma (B). Speciﬁcally, the node size is proportional to the number of papers where these molecules have been studied, while the edge width is proportional to the number of documents where two molecules have been described together. The central and biggest node corresponds to HOXB7. Proteins and miRNAs described in this review are represented as orange spheres and pink quadrangles, respectively. Protein pathways are visualized in green (activation), red (inhibition), or blue (binding information). The networks were generated using the web platform tool ProteinQuest (PQ; http://www.proteinquest.com) and visualized using Cytoscape (43).

Other solid cancers cervical cancer. Besides a number of deregulated miRNAs, miR- Numerous independent studies unanimously reported HOXB7 196b was downregulated in cervical cancer tissues and cell lines deregulation in several other types of cancer, characterized by and was associated with worse DFS in patients treated with HOXB7 overexpression in tumor tissues in relation to their chemoradiation (25). This study and previous data reporting the normal counterparts. Among these diseases, we will focus on HOXB7-based induction of VEGF in breast cancer (13) together gastrointestinal, gynecological tumors, and oral carcinomas as highlight a novel miR-196b, HOXB7, VEGF axis, raising the well as lung carcinomas. speculation on the potential efficacy of an antiangiogenic thera- In colorectal cancer, one of the most prevalent and incident peutic strategy for cervical cancer. cancers worldwide, the first study reporting altered HOXB7 In the oral cavity, HOXB7 expression was detected at levels mRNA levels goes back to 1993 (21). Only recently, HOXB7 significantly higher in oral squamous cell carcinomas (OSCC) expression was shown to be significantly correlated with the than in normal mucosa. De Souza and colleagues demonstrated invasive and aggressive characteristics of human colorectal cancer the capability of HOXB7 to promote a proliferative phenotype and, therefore, associated with a poor clinical outcome (22). correlating with features related to poor prognosis in OSCC Also, in pancreatic ductal adenocarcinoma (PDAC), one of the patients (26). Finally, a recent study confirmed significant asso- most lethal types of cancer with an overall 5-year survival rate ciation of HOXB7 expression with regional lymph nodes involve- below 4% (23), HOXB7 was found to be overexpressed and ment and clinical stage in oral and oropharyngeal squamous cell capable of augmenting invasiveness, correlating with regional carcinoma (27). Additional information was presented by Di lymph-node dissemination and worse overall survival (24). Gene Pietro and colleagues that demonstrated the correlation of profiling analyses showed, among those genes modulated by HOXB7 expression in Barrett esophagus, a metaplasia of the HOXB7, the induction of GBP1, previously shown as a positive distal esophagus that predisposes to esophageal adenocarci- effector of tumor cell invasion in glioblastoma, and the decrease noma, with levels of the epigenetic histone marks H3K27me3 of CCBP2, a chemokine decoy receptor (24). Further insight into and AcH3 at gene regulatory regions (6). PDAC biology was provided by a study on miRNAs. Among HOXB7 has also been included in a four-gene diagnostic miRNAs linked with tumor grade and venous invasion, miR- signature (CLDN4, HOXB7, TMSB4, and TTR) that can distin- 337 was found inversely correlated with HOXB7 in 44 cases of guish liver tissues of cholangiocarcinoma from hepatocellular PDAC patients retrospectively examined, and, in turn, with stage, carcinoma and from benign biliary liver diseases (28). lymph node status, and prognosis, thus suggesting a tumor HOXB7 was demonstrated to be epigenetically modulated by suppressor action played by miR-337 through the negative reg- the long noncoding RNA (lncRNA) TUG1 in lung cancer, the most ulation of HOXB7 (9). But no mechanistic insights were offered. A frequent cause of cancer-related death worldwide (8). Specifically, miRNA-dependent regulation of HOXB7 was also reported in in non–small cell lung cancer (NSCLC), TUG1 was reported to be

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Errico et al.

downregulated and associated with a poor prognosis. Conversely, hyperphosphorylation of EGFR, activation of p44 MAPK, and ER HOXB7 was found to be upregulated in NSCLC tissues, with this phosphorylation at Ser-118 (3). Further, in a recent paper, Jin and inverse correlation relying on TUG1 association with PRC2 pro- colleagues demonstrated that the HOXB7/ER complex promoted tein complexes characterized by histone methyltransferase activ- the expression of ER-target genes including HER2 through recruit- ity. The authors proposed a p53/TUG1/PRC2/HOXB7 pathway as ment of ER coactivators to their binding sites in TAM-resistant a target for NSCLC diagnosis and therapy (8). breast cancer cells (19). The upregulation of HOXB7 was attrib- uted to direct repression of miR-196a by stabilized MYC in TAM- Cofactors That Enhance HOXB7 Activity resistant cells. Upregulation of miR-196a or depletion of HOXB7 in TAM-resistant cells restored tamoxifen sensitivity by decreasing It is well known that HOX transcription factors require cofac- expression of HER2 and ER target genes. Also, inhibition of MYC tors for strengthening the affinity and specificity of binding to the synergized with HER2-targeted therapies (trastuzumab) to target sites. In this regard, in breast cancer and melanoma, achieve tumor regression (19). Furthermore, coexpression of functional requirement of PBX cofactors for the oncogenic activity HOXB7, HER2, and MYC was prognostic of poor overall and þ of HOXB7 has been demonstrated. In a breast cancer model, the relapse-free survival in patients with ER breast cancer who introduction of a dominant-negative PBX1 mutant, PBX1NT, received endocrine therapy. These findings supported HOXB7's interfered with the HOXB7-induced aggressive phenotype by role as an ER cofactor and suggested that targeting the MYC– increasing apoptosis, reducing cell cycling, and upregulating HOXB7–HER2 pathway may limit resistance to endocrine therapy þ p16 and p53 (29). HOX proteins achieve DNA sequence speci- in ER breast cancer (19). In-depth studies are needed to inves- ficity by interacting with DNA-binding proteins acting as cofactors tigate whether other RTK signaling pathways are involved in (4). Among these, the PBX family members appeared as prefer- HOXB7-mediated resistance to TAM. ential binding partners of HOXB7 in melanoma (30, 31). Along Inhibition of the HOX/PBX interaction has been proposed as a these lines, Errico and colleagues reported the activating role of therapeutic strategy. To this end, a small cell-permeable peptide the HOXB7/PBX2 complex on miR-221 and miR-222 transcrip- (HXR9) has been shown to trigger apoptosis in different cancer tion, supporting a model involving an intricate and reciprocal cells, including melanoma, antagonizing the interaction between interplay between HOXB7, their cofactors and miRNAs (5). These HOX and PBX proteins, and disrupting the binding of these two clustered miRNAs are highly upregulated in a variety of solid proteins to DNA consensus sites (37). In this regard, the study tumors. Specifically, in melanoma miR-221 and miR-222 by Errico and collaborators suggests that the direct inhibition of enhance tumorigenicity by targeting, among many other mole- miR-221 and miR-222 by antagomiRNA treatment and/or the cules, p27Kip1, ETS-1, c-KIT receptor, and c-FOS, thus leading to disruption of HOXB7/PBX2 dimers might represent innovative enhanced proliferation, dissemination, differentiation blockade, approaches for translation into the clinical setting (5). and apoptosis reduction (5, 31). Epithelial ovarian carcinoma is the fourth most common cause Another HOXB7-interacting partner that contributes to geno- of cancer-related death in women in the developed world, where it mic stability is poly(ADP)ribose polymerase-1 (PARP-1), an is also the leading cause of death from gynecological malignancies enzyme that undergoes rapid activation in response to DNA (38). In the last two decades, advances in the understanding of damage (32). Indeed, Wu and colleagues further defined the ovarian cancer immunogenicity have opened the door to immu- protein/protein interaction of HOXB7 with PARP-1. Upon notherapeutic approaches to ovarian cancer treatment. The this binding, poly(ADP-ribosyl)ation of HOXB7 represses its humoral immune response elicited by TAAs could also generate transcriptional and DNA binding capabilities. In line with this, circulating autoantibodies possibly representing novel biomar- the inhibition of PARP-1 restored HOXB7 transactivation (32). kers for cancer diagnosis, prognosis, monitoring, and prediction PARP-1 was also reported to modulate the activity of Yin Yang 1 of response to chemotherapy. In normal individuals and in non- (YY1), a transcription factor involved in the positive transcrip- cancer conditions, these antibodies are generally absent or present tional regulation of the HOXB7 gene by direct interaction with its in very low titers; thus, there is a growing interest in evaluating promoter (33). serum autoantibodies against TAAs as biomarkers in cancer immunodiagnosis (39). This idea was supported by Erkanli and Clinical Implications colleagues, who developed a serum assay evaluating the antibody response to a panel of TAAs for cancer diagnosis. Specifically, they Several findings have paved the way to investigations on demonstrated that measuring specific autoantibodies in a three- HOXB7 as a potential druggable target. Despite major advances member panel of TAAs (p53, NY-CO-8, and HOXB7), in addition in breast cancer treatment and management, and successful to serum CA-125, yielded a reasonable sensitivity and specificity treatment of ER-positive breast cancer with tamoxifen and aro- in discriminating between epithelial ovarian carcinoma patients matase inhibitors, one third of women with estrogen receptor a and healthy controls (40). Nonetheless, the effectiveness of (ER)–positive breast cancer suffer from recurrent disease within HOXB7 as a TAA remains an unconfirmed finding. 15 years (34). As EMT has been observed in tamoxifen (TAM)- resistant MCF-7 breast cancer cells (35, 36) and given the association between HOXB7 and EMT in breast cancer (11), HOXB7 Future Perspectives protein might possibly play a role in tamoxifen resistance and Although in recent times an enormous body of basic and ensuing tumor progression. Evidence supporting this hypothesis translational research investigations has identified a large number was elucidated by Jin and collaborators through work that dem- of potential biomarkers, a number of cancers are diagnosed at onstrated that HOXB7 overexpression conferred TAM resistance advanced stages and patient survival has not significantly þ to ER breast cancer cells through HOXB7-dependent transcrip- improved. The identification of additional, more informative tional induction of EGFR (3). In addition, the authors observed biomarkers is, therefore, of outmost importance.

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HOXB7 Action in Solid Tumors

Over the last few decades, a number of genes and noncoding itating tumor progression in many solid tumors. If future work RNAs in the HOX clusters have been found to be regulated in confirms its utility as a biomarker and its possible facile different tumor types. To therapeutically target HOX proteins detection in easily accessible tissues (i.e., plasma, serum, spu- has attractive clinical implications, but it has been challenging tum,andurine),HOXB7couldeventually represent a funda- to attain a high level of specificity due to their extreme homol- mental tool in the oncologist's armamentarium. The studies ogy with other HOX proteins. However, current advances in reviewed here raise hope regarding HOXB7's potential role in gene therapy and computational biology might contribute early diagnosis, direct targeting and selection of targeted ther- substantially in overcoming this restriction. By using siRNAs/ apeutic approaches. shRNAs or RNA targeting tools (ribozymes, aptamers, ASOs, lncRNAs, and miRNAs) delivered as nanoparticles, stable, selective, and efficient knockdown or overexpression of genes Disclosure of Potential Conflicts of Interest can be achieved. In addition, pharmaceutically designing drugs No potential conflicts of interest were disclosed. that inhibit the interaction between HOX proteins and their partners is a promising approach to inhibit their function (5, Grant Support 41, 42). As most of the data on HOXB7 expression and function This work was supported by grants from the Italian Ministry of Health were derived from retrospective analyses of patient tumors, (RF-2010-2310494) and the Italian Association for Cancer Research (AIRC sometimes without adequate treatment information, further IG13247) to A. Care and SKCCC Core grant P30 CA006973 to S. Sukumar. prospective validation extended to larger, more controlled cohort of patients will be required. Nevertheless, there is strong Received December 17, 2015; revised February 18, 2016; accepted February evidence already that HOXB7 plays a dominant role in facil- 20, 2016; published OnlineFirst April 20, 2016.

References 1. Duboule D. The rise and fall of Hox gene clusters. Development 2007;134: 14. Care A, Felicetti F, Meccia E, Bottero L, Parenza M, Stoppacciaro A, et al. 2549–60. HOXB7: a key factor for tumor-associated angiogenic switch. Cancer Res 2. Shah N, Sukumar S. The Hox genes and their roles in oncogenesis. Nat Rev 2001;61:6532–9. Cancer 2010;10:361–71. 15. Makiyama K, Hamada J, Takada M, Murakawa K, Takahashi Y, Tada M, et al. 3. JinK,KongX,ShahT,PenetMF,WildesF,SgroiDC,etal.TheHOXB7 Aberrant expression of HOX genes in human invasive breast carcinoma. protein renders breast cancer cells resistant to tamoxifen through Oncol Rep 2005;13:673–9. activation of the EGFR pathway. Proc Natl Acad Sci U S A 2012;109: 16. Chen H, Lee JS, Liang X, Zhang H, Zhu T, Zhang Z, et al. Hoxb7 inhibits 2736–41. transgenic HER-2/neu-induced mouse mammary tumor onset but pro- 4. Longobardi E, Penkov D, Mateos D, De Florian G, Torres M, Blasi F. motes progression and lung metastasis. Cancer Res 2008;68:3637–44. Biochemistry of the tale transcription factors PREP, MEIS, and PBX in 17. Liu S, Jin K, Hui Y, Fu J, Jie C, Feng S, et al. HOXB7 promotes malignant vertebrates. Dev Dyn 2014;243:59–75. progression by activating the TGFbeta signaling pathway. Cancer Res 5. Errico MC, Felicetti F, Bottero L, Mattia G, Boe A, Felli N, et al. The 2015;75:709–19. abrogation of the HOXB7/PBX2 complex induces apoptosis in mela- 18. Rubin E, Wu X, Zhu T, Cheung JC, Chen H, Lorincz A, et al. A role for the noma through the miR-221&222-c-FOS pathway. Int J Cancer 2013; HOXB7 homeodomain protein in DNA repair. Cancer Res 2007;67: 133:879–92. 1527–35. 6. di Pietro M, Lao-Sirieix P, Boyle S, Cassidy A, Castillo D, Saadi A, et al. 19. JinK,ParkS,TeoWW,KorangathP,ChoSS,YoshidaT,etal.HOXB7 Evidence for a functional role of epigenetically regulated midcluster HOXB is an ERalpha cofactor in the activation of HER2 and multiple ER genes in the development of Barrett esophagus. Proc Natl Acad Sci U S A target genes leading to endocrine resistance. Cancer Discov 2015;5: 2012;109:9077–82. 944–59. 7. Marcinkiewicz KM, Gudas LJ. Altered epigenetic regulation of homeobox 20. Heinonen H, Lepikhova T, Sahu B, Pehkonen H, Pihlajamaa P, Louhimo R, genes in human oral squamous cell carcinoma cells. Exp Cell Res 2014;320: et al. Identification of several potential chromatin binding sites of HOXB7 128–43. and its downstream target genes in breast cancer. Int J Cancer 2015;137: 8. Zhang EB, Yin DD, Sun M, Kong R, Liu XH, You LH, et al. P53-regulated 2374–83. long non-coding RNA TUG1 affects cell proliferation in human non-small 21. De Vita G, Barba P, Odartchenko N, Givel JC, Freschi G, Bucciarelli G, et al. cell lung cancer, partly through epigenetically regulating HOXB7 expres- Expression of homeobox-containing genes in primary and metastatic sion. Cell Death Dis 2014;5:e1243. colorectal cancer. Eur J Cancer 1993;29A:887–93. 9. Zhang R, Leng H, Huang J, Du Y, Wang Y, Zang W, et al. miR-337 regulates 22. Liao WT, Jiang D, Yuan J, Cui YM, Shi XW, Chen CM, et al. HOXB7 as a the proliferation and invasion in pancreatic ductal adenocarcinoma by prognostic factor and mediator of colorectal cancer progression. Clin targeting HOXB7. Diagn Pathol 2014;9:171. Cancer Res 2011;17:3569–78. 10. Hyman E, Kauraniemi P, Hautaniemi S, Wolf M, Mousses S, Rozenblum E, 23. Lowe AW, Olsen M, Hao Y, Lee SP, Taek Lee K, Chen X, et al. Gene et al. Impact of DNA amplification on gene expression patterns in breast expression patterns in pancreatic tumors, cells and tissues. PLoS One cancer. Cancer Res 2002;62:6240–5. 2007;2:e323. 11. Wu X, Chen H, Parker B, Rubin E, Zhu T, Lee JS, et al. HOXB7, a home- 24. Nguyen Kovochich A, Arensman M, Lay AR, Rao NP, Donahue T, Li X, et al. odomain protein, is overexpressed in breast cancer and confers epithelial- HOXB7 promotes invasion and predicts survival in pancreatic adenocar- mesenchymal transition. Cancer Res 2006;66:9527–34. cinoma. Cancer 2013;119:529–39. 12. Care A, Silvani A, Meccia E, Mattia G, Stoppacciaro A, Parmiani G, et al. 25. How C, Hui AB, Alajez NM, Shi W, Boutros PC, Clarke BA, et al. MicroRNA- HOXB7 constitutively activates basic fibroblast growth factor in melano- 196b regulates the homeobox B7-vascular endothelial growth factor axis in mas. Mol Cell Biol 1996;16:4842–51. cervical cancer. PLoS One 2013;8:e67846. 13. Care A, Silvani A, Meccia E, Mattia G, Peschle C, Colombo MP. Transduc- 26. De Souza Setubal Destro MF, Bitu CC, Zecchin KG, Graner E, Lopes MA, tion of the SkBr3 breast carcinoma cell line with the HOXB7 gene induces Kowalski LP, et al. Overexpression of HOXB7 homeobox gene in oral bFGF expression, increases cell proliferation and reduces growth factor cancer induces cellular proliferation and is associated with poor prognosis. dependence. Oncogene 1998;16:3285–9. Int J Oncol 2010;36:141–9.

www.aacrjournals.org Cancer Res; 76(10) May 15, 2016 2861

Errico et al.

27. Rivera C, Gonzalez-Arriagada WA, Loyola-Brambilla M, de Almeida OP, cer cell: a new role for G protein-coupled estrogen receptor in mediating Coletta RD, Venegas B. Clinicopathological and immunohistochemical tamoxifen resistance through cancer-associated fibroblast-derived fibro- evaluation of oral and oropharyngeal squamous cell carcinoma in Chilean nectin and beta1-integrin signaling pathway in tumor cells. Breast Cancer population. Int J Clin Exp Pathol 2014;7:5968–77. Res 2015;17:69. 28. Kraiklang R, Pairojkul C, Khuntikeo N, Imtawil K, Wongkham S, 36. Ward A, Balwierz A, Zhang JD, Kublbeck M, Pawitan Y, Hielscher T, et al. Re- Wongkham C, et al. A novel predictive equation for potential diag- expression of microRNA-375 reverses both tamoxifen resistance and nosis of cholangiocarcinoma. PLoS One 2014;9:e89337. accompanying EMT-like properties in breast cancer. Oncogene 2013;32: 29. Fernandez LC, Errico MC, Bottero L, Penkov D, Resnati M, Blasi F, et al. 1173–82. Oncogenic HoxB7 requires TALE cofactors and is inactivated by a dom- 37. Morgan R, Boxall A, Harrington KJ, Simpson GR, Gillett C, Michael A, et al. inant-negative Pbx1 mutant in a cell-specific manner. Cancer Lett Targeting the HOX/PBX dimer in breast cancer. Breast Cancer Res Treat 2008;266:144–55. 2012;136:389–98. 30. Shiraishi K, Yamasaki K, Nanba D, Inoue H, Hanakawa Y, Shirakata Y, et al. 38. Chester C, Dorigo O, Berek JS, Kohrt H. Immunotherapeutic approaches to Pre-B-cell leukemia transcription factor 1 is a major target of promyelocytic ovarian cancer treatment. J Immunother Cancer 2015;3:7. leukemia zinc-finger-mediated melanoma cell growth suppression. Onco- 39. Zhu Q, Liu M, Dai L, Ying X, Ye H, Zhou Y, et al. Using immunoproteomics gene 2007;26:339–48. to identify tumor-associated antigens (TAAs) as biomarkers in cancer 31. Felicetti F, Errico MC, Bottero L, Segnalini P, Stoppacciaro A, Biffoni M, immunodiagnosis. Autoimmun Rev 2013;12:1123–8. et al. The promyelocytic leukemia zinc finger-microRNA-221/-222 path- 40. Erkanli A, Taylor DD, Dean D, Eksir F, Egger D, Geyer J, et al. Application of way controls melanoma progression through multiple oncogenic mechan- Bayesian modeling of autologous antibody responses against ovarian isms. Cancer Res 2008;68:2745–54. tumor-associated antigens to cancer detection. Cancer Res 2006;66: 32. Wu X, Ellmann S, Rubin E, Gil M, Jin K, Han L, et al. ADP ribosylation by 1792–8. PARP-1 suppresses HOXB7 transcriptional activity. PLoS One 2012;7: 41. Li CH, Chen Y. Targeting long non-coding RNAs in cancers: progress and e40644. prospects. Int J Biochem Cell Biol 2013;45:1895–910. 33. Oei SL, Shi Y. Poly(ADP-ribosyl)ation of transcription factor Yin Yang 1 42. Brock A, Krause S, Li H, Kowalski M, Goldberg MS, Collins JJ, et al. under conditions of DNA damage. Biochem Biophys Res Commun 2001; Silencing HoxA1 by intraductal injection of siRNA lipidoid nanopar- 285:27–31. ticles prevents mammary tumor progression in mice. Sci Transl Med 34. Brown RJ, Davidson NE. Adjuvant hormonal therapy for premenopausal 2014;6:217ra2. women with breast cancer. Semin Oncol 2006;33:657–63. 43. Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, et al. 35. Yuan J, Liu M, Yang L, Tu G, Zhu Q, Chen M, et al. Acquisition of epithelial- Cytoscape: a software environment for integrated models of biomolecular mesenchymal transition phenotype in the tamoxifen-resistant breast can- interaction networks. Genome Res 2003;13:2498–504.

2862 Cancer Res; 76(10) May 15, 2016 Cancer Research

The Widening Sphere of Influence of HOXB7 in Solid Tumors

Maria Cristina Errico, Kideok Jin, Saraswati Sukumar, et al.

Cancer Res 2016;76:2857-2862. Published OnlineFirst April 20, 2016.

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