The Met oncogene and basal-like breast cancer: another culprit to watch out for?

Recent findings suggest the involvement of the MET oncogene, encoding the tyrosine kinase receptor for hepatocyte growth factor, in the onset and progression of basal-like breast carcinoma. The expression profiles of basal-like tumors - but not those of other breast cancer subtypes - are enriched for gene sets that are coordinately over-represented in transcriptional signatures regulated by Met. Consistently, tissue microarray analyses have revealed that Met immunoreactivity is much higher in basal-like cases of human breast cancer than in other tumor types. Finally, mouse models expressing mutationally activated forms of Met develop a high incidence of mammary tumors, some of which exhibit basal characteristics. The present review summarizes current knowledge on the role and activity of Met in basal-like breast cancer, with a special emphasis on the correlation between this tumor subtype and the cellular hierarchy of the normal mammary gland.


The Met receptor in breast cancer
In past years, a large number of clinical studies have described Met-receptor overexpression and pathway hyperactivation in tissues derived from breast cancer patients, and have found a strong relationship between high HGF/Met signaling and tumor progression (Table 1). Indeed, the HGF content in breast tumor tissue correlates with the aggressive phenotype, being higher in invasive ductal carcinomas than in ductal carcinomas in situ and benign hyperplasia [21,22]. In normal mammary tissue HGF is expressed by stromal cells surrounding the epithelial compartment, whereas in cancer the ligand can be produced de novo by carcinoma cells that also express the receptor, thus generating an autocrine loop that predicts poor prognosis [16]. Moreover, in many cases HGF and Met are co-expressed in correspondence of the advancing margins of mammary tumors, a fi nding that goes along with high histological grade and high proliferative index [23]. In axillary lymph node-negative patients, Met overexpression is signifi cantly associated with reduced survival, with a 5-year survival rate of 62% compared with 97% of Met low-expressing patients. Th e follow-up of these patients revealed that in many cases Met expression was negligible at the time of diagnosis but increased in late recurrences, thus suggesting a possible selection of Met-overexpressing clones in relapse and metastasis [24]. Clinical data are supported by animal models of Metdriven mammary tumorigenesis: transgenic mice in which HGF has been specifi cally targeted to the mammary epithelium using the Whey-acidic-protein promoter display a hyperplastic ductal tree with multi focal invasive tumors [25]. Similarly, primary cultures of mammary cells overexpressing Met develop nonprogres sive neoplasms upon orthotopic implantation in recipient mice; such lesions are able to progress to adeno carcinomas when the proto-oncogene Myc is ectopically overexpressed together with Met [26].

Molecular classifi cation of human breast cancer recalls the cellular hierarchy of the normal mammary gland
Human breast cancer is a heterogeneous disease that comprises a variety of pathologies with diff erent histological features and clinical outcomes. On the basis of Met is an α/β heterodimer formed by a completely extracellular α subunit and a transmembrane β subunit that contains the tyrosine kinase activity. The extracellular region of Met encompasses a large Sema domainwhich spans the α subunit and part of the β subunit, folding into a β-propeller structure -a cysteine-rich domain and four repeats of an unusual type of immunoglobulin-like domain. The intracellular portion of Met includes the kinase domain -with two catalytic tyrosines (Tyr1234 and Tyr1235) that enhance the receptor enzymatic activity following transphosphorylation -and key tyrosine residues in the carboxy-terminal tail (Tyr1349 and Tyr1356). Phosphorylation of these distal tyrosines creates docking sites for several interactors, many of which are schematized here. Recruitment of these signaling eff ectors activates downstream pathways that together enable biological execution of the invasive growth process. The Ras-Erk/mitogen-activated protein kinase (MAPK) cascade launches a program of transcriptional modulation that involves changes in the expression of cell-cycle regulators and extracellular matrix proteinases. Ras also stimulates the Rac1/Cdc42-PAK pathway, which, together with the Gab1-Crk-C3G-Rap1 axis, regulates the activity of cytoskeletal and adhesion molecules such as cadherins, Arp, N-WASP, paxillin, integrins and focal adhesion kinase. The Gab1-phosphoinositide 3-kinase (PI3K)-Akt pathway encourages cell survival by inhibiting the proapoptotic molecule Bad and the apopototic eff ector caspase 9.
gene expression profi les obtained from cDNA microarray analysis of a large set of tumor samples, Sorlie and colleagues defi ned a new molecular classifi cation of human breast cancers [27]. According to this classifi cation, breast tumors have been clustered into fi ve diff erent subtypes: luminal A, luminal B, Her2-overexpressing, normal-like and basal-like. Th is classifi cation refl ects the characteristics of the cell populations that are present in the normal epithelium of the mammary gland. In fact, besides highlighting the molecular heterogeneity of breast tumor subtypes, the transcriptional profi les revealed a molecular/phenotypic connection between the transformed cells and the normal epithelial counterpart. Based on this observation, it has been proposed that the diff erent types of breast cancer have their cell of origin in the diff erent subpopulations that constitute the normal mammary gland under physiological conditions.

The cell hierarchy of the normal mammary gland
Th e mature mammary epithelium is composed of three main epithelial cell types: the basal/myoepithelial cells, which line the outer side of the ducts; and the luminal cells, which are further distinguished into ductal and alveolar elements and form the inner side of the ducts and the alveoli, respectively. According to molecular profi ling, it is assumed that the luminal subtype arises from cells belonging to the luminal lineage, whilst the basal subtype is supposed to derive from less diff er entiated cells of the gland -such as stem/progenitor cellsthat are normally located within the basal/myoepithelial compartment and exhibit basal phenotypic markers.
Th e epithelial cells of the mammary gland are organized in a hierarchical manner, with stem cells and progenitor cells giving rise to all the diff erent lineages that are present in the mature gland. Th e stem cells, also called mammary repopulating units, are capable of selfrenewal and generate all of the cellular types that make up the mammary gland [28]. Th e existence of a stem cell population has been postulated for a long time because of the ability of the mammary gland to go through several cycles of proliferation and involution during pregnancies, and due to the fact that the transplantation of mammary fragments into the fat pad of receiving animals is suffi cient to form a mature mammary tree [29,30]. Th e immediate progeny of stem cells identifi es the compartment of progenitors, which is composed of actively proliferating cells endowed with a limited diff erentiation potential. Progenitor cells are also called mammary colony-forming units because of their ability to effi ciently generate clonal aggregates when cultured in vitro [31].
Th e recent identifi cation of surface markers characteristic of the distinct subpopulations, from undiff er entiated cells to mature cells, allowed their prospective isolation and biological characterization. Two indepen dent  [82] High levels of Met and HGF in node-negative breast cancer Tumor progression and poor patient outcome Lengyel and colleagues [83] Met overexpression in node-positive breast cancer Disease progression and decrease in disease-free survival Charafe-Jauff re and colleagues [43] Met overexpression in breast cancer cell lines Basal-like phenotype Lindemann and colleagues [84] Imbalance in Met expression between tumor and normal Aggressive ductal carcinoma in situ tissue Eichbaum and colleagues [85] High HGF serum levels Liver metastatic colonization from breast cancer Garcia and colleagues [45] Met overexpression in tissue microarrays Poor prognosis, basal-like phenotype Finkbeiner and colleagues [49] Transcriptional upregulation of Met Anchorage-independent growth of basal-like breast cancer cells groups were able to isolate mouse mammary repopulating units and progenitor cells on the basis of the diff erential expression of the surface markers CD24, CD49f and CD29. Stingl and colleagues identifi ed mammary repopulating units on the basis of a CD24 + CD49f high phenotype, while Shackleton and coworkers defi ned the stem cell subpopulation as Lin -CD24 + CD29 high [31,32]. Both groups demonstrated the ability of these cells to selfrenew and to generate a completely functional mammary gland even after transplantation of one single cell. A subset of progenitors committed to the luminal lineage was isolated based on the expression of CD61 and low levels of CD133 and Sca1. Th ese cells can terminally diff erentiate into mature luminal cells, which lose CD61 expression and increase expression of CD133 and Sca1 [33,34].

Mammary epithelial subpopulations and types of breast cancer
As mentioned before, the diff erent types of breast cancer probably refl ect a distinct cell of origin present along the hierarchical organization of the normal mammary gland. Indeed, the luminal subtype is characterized by high expression of genes of the luminal compartment, including estrogen receptor alpha (ERα), cytokeratin 18, the transcription factor GATA3 and estrogen-regulated genes; this group is further subdivided into type A and type B, which diff er for the level of expression of ERα, the proliferation index (assessed by Ki67 staining), and the clinical outcome [35]. Th e Her2 subtype is characterized by overexpression of the Her2 protein on the cell membrane, due to genomic amplifi cation of the region 17q22.24 that includes the genes coding for Her2 and growth factor receptor-bound protein 7. Th e normal breast signature defi nes a group of tumors with high expression of genes of adipose cells and other nonepithelial cell types, as well as low levels of luminal markers. Finally, tumors belonging to the basal-like subgroup express high levels of basal markers, such as cytokeratins 5/14/17 and laminin, and do not express ERα, progesterone receptor and Her2. Notably, it was initially assumed that the cell of origin of this tumor subtype was to be found in the stem cells of the basal compartment. Recent gene expression profi ling of the diff erent subpopulations in the human normal mammary gland and analysis of tumors with basal-like features, however, showed that this tumor phenotype appears to be more similar to the gene signature derived from the luminal progenitor population [36]. Th e molecular classifi cation of breast cancer has an important prognostic value: the single subtypes have diff erent prognosis and show diff erent responsiveness to specifi c therapies. Th e luminal tumors are those with a better outcome and a wider possibility of treatment: ERα is preferentially expressed in terminally diff erentiated luminal cells and, accordingly, luminal tumors exhibit a diff erentiated morphology with almost benign features. More importantly, the mitogenic activity of estrogen can be counteracted by endocrine agents such as tamoxifene and aromatase inhibitors [37,38]. In the case of the Her2 group, tumors are endowed with a more aggressive pheno type, but overexpression of Her2 makes the majority of such tumors highly responsive to Her2 inhibition obtained with the specifi c monoclonal antibody trastuzumab (Herceptin) [39].
Among the diff erent subgroups, the basal-like breast cancers (BLBCs) are those that have the worst clinical outcome: they represent 15 to 20% of human breast cancer and are characterized by an aggressive phenotype with high histological grade, pushing borders, large areas of necrosis and high mitotic indexes. Th e majority of BLBCs does not express hormone receptors (ERα and progesterone receptor) and is negative for Her2; they are therefore called triple-negative tumors [40,41]. Th eir mole cular features render these tumors especially diffi cult to treat with anti-hormonal approaches; moreover, the lack of understanding of the genes and processes involved in transformation and progression of this tumor subtype makes it diffi cult to target with last-generation tailored therapies. As for conventional chemotherapeutics, BLBCs appear to be more sensitive than luminal subtypes to neoadjuvant anthracycline-based regimens, which could be explained by the fact that anthracyclines work effi ciently on hyperproliferating cells and that the proliferation-related gene set is highly represented in this subtype; yet BLBCs have poor survival due to higher relapse rate following incomplete pathologic response [42]. In this scenario, the identifi cation of causative, targetable biomarkers for the basal subtype, which could be challenged for prospective therapies, remains an unmet clinical need.

Met and basal-like breast cancer
Together with patient-derived material, breast cancer cell lines have been utilized as tools to identify new markers for the study of breast tumor subtypes. Both genomewide expression profi ling and proteomic approaches led to the classifi cation of cell lines in two major clusters: the luminal group and the basal group. Similar to data obtained from surgical specimens, genes overexpressed in the luminal cluster include ERα, GATA3, cytokeratin 19 and genes associated with ER-positive status, such as cytokeratin 8, cytokeratin 18 and mucin 1. Th e basal cluster is typifi ed by high expression of cytokeratins 5/14/17, integrin α 6 , integrin β 4 , CD44, CD10 and caveolin 1. Interest ingly, these large-scale analyses allowed the identifi cation of new basal markers: together with other tyrosine kinases, including the epidermal growth factor receptor (EGFR) and c-Kit, Met emerged as one of the most diff erentially regulated genes in the basal cluster versus the luminal cluster [43,44].
Th ese results have been confi rmed in tissue microarraybased clinical studies on a large number of breast carcino mas [44][45][46][47]. A cohort of 930 tumor samples, subdivided according to patient survival and lymph node status, was screened for expression of Met together with proteins known to be representative of the basal phenotype (cytokeratin 5, cytokeratin 6, caveolin 1, c-Kit, p63). High Met staining was found in tumors from deceased patients with highly invasive malignancies. Importantly, Met overexpression was consistently associa ted with co-expression of basal markers, thus pinpointing Met as an additional constituent of the basal phenotype [45]. Similar fi ndings were obtained in an inde pendent tissue microarray containing 1,600 specimens from 547 patients with early breast cancer [44] and in a more limited subset of metastatic tumors [46].

Mechanistic insights
A mechanistic link between Met and BLBCs is highlighted by the observation that receptor overexpression correlates with high expression levels of the transcription factor Y-box binding protein-1 (YB-1). An oncogenic transcriptional/translational factor, YB-1 was originally identifi ed by screening an expression library for DNAbinding proteins able to interact with the EGFR enhancer and with the Her2 promoter region [48]. A recent survey of candidate DNA-binding regions showed that YB-1 can bind to more than 6,000 promoters, among which promoters of kinases and growth factor receptors are highly repre sented [49]. YB-1 is highly expressed in more than 70% of basal-like cancers, and its expression correlates with poor survival and high risk of relapse [50]. YB-1 is also expressed in normal mammary bipotent progenitor cells, but the level of the protein is much lower than that observed in tumors. Th is diff erential expression is in line with a functional role for this transcription factor in tumor onset and progression.
Among the transcriptional targets of YB-1 there are several genes representative of the basal-like signature, including Met [49,51]. Chromatine immunoprecipitation analysis indicated that YB-1 binds directly to the Met promoter in a region that resides -1,080 bp from the translational starting site, thus driving Met expression. YB-1 and Met are both highly expressed in cell lines belonging to the basal cluster, and the downmodulation of YB-1 produces a reduction in the levels of Met, together with an impairment of cell proliferation and anchorage-independent growth. Neither YB-1 nor the Met gene appeared to be amplifi ed in basal cell lines, indicating that the main mechanism leading to overexpression of both molecules is probably based on transcriptional/translational regulation [49].

Met and mouse models of basal-like breast cancer
Recently, two diff erent mouse models of conditional expression of oncogenic Met variants in the mammary gland demonstrated a causal role for Met in the onset of diverse types of mammary tumors, including BLBCs. In the fi rst model, the oncogenic mutant of Met, containing activating missense mutations within the tyrosine kinase domain, was knocked-in downstream from the Met endogenous promoter [52]; in the second model, transforming isoforms of Met were transgenically expressed in the mammary epithelium under the control of the mouse mammary tumor virus promoter [53]. Oncogenic Met knock-in mice developed a spectrum of mammary cancers (solid adenocarcinomas, adenosqua mous carcinomas, and myoepitheliomas), with some of them displaying histological, cytogenetic, and phenotypic charac teristics typical of basal-like cancers, such as cytokeratin 5 expression and absence of progesterone receptor and Her2 expression. Similarly, transgenic mice with mouse mammary tumor virus promoter-driven expression of mutant Met developed tumors with a high degree of morphological heterogeneity, including solid/ luminal features and lesions with papillary, scirrhous, adenosquamous, or spindle-cell phenotypes. Gene expression profi ling for this latter mixed-pathology group revealed that such tumors have an enrichment of basal markers as well as genes associated with epithelialmesenchymal transition; for instance, Snail [53].
Analysis of Met expression in a cohort of human breast cancer samples showed that tumors with the highest levels of Met correlate with the basal subtypes, and breast cancers with a transcriptional signature indicative of Met activation mainly fall within the basal cluster. Among these tumors, those with active Met expression profi ling had a worse prognosis and a shorter disease-free survival [52]. Th ese transcriptional data have been recently corroborated by genome-wide copy number analysis in BLBC cell lines: although focal amplifi cation of MET was not detected, specifi c enrichment of the HGF/Met pathway was refl ected in frequent copy number gains and overexpression of key adapter molecules and downstream signal transducers [54].
In sum, studies performed in cell lines, in patientderived material, and in animal models provide a clear indication that Met is preferentially expressed (or is mainly active) in BLBCs with respect to other subtypes of breast cancer. While this is certainly true, it should be noted that Met overexpression can be observed sporadically also in nonbasal-like tumors: for example, increased levels of Met are detectable in some cases of Her2-positive and ER-positive mammary carcinomas [52,53]. Something similar also applies to other tyrosine kinase receptors, including EGFR and c-Kit: their expression strongly correlates with BLBCs, but these oncogenes are not uniquely expressed in this tumor subtype [40]. Indeed, when taken individually, none of the markers of the basal cluster can function as independent predictors. Th ese markers do, however, comprehensively defi ne an algorithm that signifi cantly segregates BLBCs versus other breast cancer entities.

Met, BRCA1 mutated cancer and the basal phenotype
Th e basal-like group also includes a type of familial breast cancer that arises in BRCA1 mutation carriers. Th e presence of germline BRCA1 mutations increases the risk of developing breast cancer and ovarian cancer in young women [55]. Th e pathologic and molecular features of breast cancers arising in BRCA1 mutation carriers resemble those observed in the basal-like subtype: such tumors have a high histological grade, high proliferation indexes and pushing borders, and lack ERα, progesterone receptor and Her2 expression [56,57].

The molecular function of BRCA1
One of the main activities of BRCA1 involves the regulation of DNA double-strand break repair through the process of homologous recombination. Tumor cells that lack BRCA1 expression are hence relatively sensitive to DNA-damaging agents [58]. Th ese cells are particularly responsive to chemical inhibition of poly(ADP-ribose) polymerase, which leads to the accumulation of DNA single-strand breaks that are then converted into DNA double-strand breaks during replication [59][60][61]. In normal cells, the DNA double-strand breaks are fi xed by repair mechanisms involving BRCA1; in cells lacking BRCA1, these lesions are repaired by error-prone systems, such as nonhomologous end joining, with the consequent accumulation of mutations and complex chromosomal rearrangements that ultimately lead to cell death [62].
Tumors arising in BRCA1-mutated patients are characterized by the presence of somatic inactivating mutations of p53 [63,64]. Genomic instability caused by BRCA1 loss would normally lead to cell-cycle arrest through the p53mediated DNA damage checkpoint, and eventually to apoptosis. Th e concomitant loss of function of p53 aff ords cells the ability to bypass this checkpoint block and to continue unscheduled proliferation in the face of severe chromosomal instability. In this condition, the ensuing occurrence of secondary lesions is likely to contribute to full-blown neoplastic transformation [65].

Met, BRCA1 and mouse models of basal-like breast cancer
Met overexpression has been associated with experimental tumors arising in a BRCA1 mutated context, specifi cally in a mouse model in which BRCA1 and p53 were conditionally deleted in the mammary epithelium [65]. A genome-wide screening of tumors developed in these mice revealed that the most common genetic alteration was amplifi cation of the Met locus (73% of cases). As a consequence, these tumors expressed high levels of Met mRNA and protein. Th e amplifi cation was associated with extra-chromosomal double minutes; these are unstable genomic elements that were detected in vivo by fl uorescence in situ hybridization analysis of mouse-derived tumors but were rapidly lost in primary cultures, probably because double minutes are maintained only in the presence of in vivo selection pressures within the breast microenvironment.
It is noteworthy that Met amplifi cation in the form of extrachromosomal double minutes is also a primary alteration in the mutant Met knock-in mice that develop basal-like breast tumors [52]. Together, these fi ndings suggest that Met amplifi cation may be a common event in murine mammary tumorigenesis. Focal amplifi cation of the MET gene, however, is not a common fi nding in human breast cancer: interphase fl uorescence in situ hybridization performed on a human breast cancer tissue microarray did not reveal any amplifi cation of the Met genomic locus [65], and this genetic alteration has not so far been reported for BRCA1 mutation carriers. A more frequent occurrence is low-grade polysomy (three to fi ve copies) of chromosome 7 -where the MET locus resideswhich is detected in approximately 25% of human ductal infi ltrating carcinomas [66].

Met and epidermal growth factor receptor in basal-like breast cancer
Another tyrosine kinase that phenotypically marks basallike breast tumors is EGFR. Similar to Met, EGFR is highly expressed in the majority of BLBCs in vivo and exerts proliferative and anti-apoptotic functions in cultured basal-like breast cancer cells [43]. In preclinical studies, EGFR inhibition can potentiate cisplatin-induced apoptosis in cultured basal-like breast cells [67].

Clinical trials with epidermal growth factor receptor inhibitors
Based on these observations, clinical trials have been designed to study the eff ect of EGFR inhibition in patients with BLBC. Two studies completed to date have provided interlocutory results. TBCRC 001 was a randomized phase II trial evaluating the role of EGFR inhibition for triple-negative metastatic breast cancer. In this study, eligible women received the anti-EGFR monoclonal antibody cetuximab combined with carboplatin, or received cetuximab alone with a planned crossover to carboplatin at progression. Cetuximab alone showed a low response rate and this trial arm was closed before time; response to the combination of cetuximab plus carboplatin was 17%, with clinical benefi t seen in 29% of a pretreated population [68]. A similar study examining irinotecan plus carboplatin with or without cetuximab showed a modestly higher response rate (from 30 to 49%) with the cetuximab combination [68].
Th ese interim data together indicate that targeted therapies against EGFR in breast tumors appear to be poorly eff ective with respect to other types of cancer in which EGFR deregulation has been documented, such as lung cancer and colon cancer [69][70][71]. Th is lack of eff ect could be due, at least in principle, to the presence of concomitantly active signal transduction pathways ema nating from other tyrosine kinase receptors, including Met.

The Met-epidermal growth factor receptor connection
Several pieces of evidence point to an intimate relationship between EGFR and Met signaling, both in physio logical settings, such as mammary gland morphogenesis [72], and in pathologic conditions, including cancer progression and resistance to targeted therapies. In nonsmall-cell lung carcinomas, for example, the onset of secondary resistance to EGFR inhibition relies, among other things, on the acquisition of MET gene amplification and consequent protein over expres sion, which leads to activation of signal transduction cascades that compensate for EGFR blockade and sustain tumor maintenance [73][74][75]. Something similar might also occur in mammary tumors. Met and EGFR are both overexpressed in breast cancer cell lines endowed with a basal-like subtype molecular profi le [42]. In this context, resistance to the EGFR inhibitor gefi tinib occurs because EGFR is trans-phosphorylated via a Met/Src-mediated signaling pathway. Accordingly, cancer cell proliferation can be impaired by combined neutralization of EGFR and Met signals [76].
Together with Met and EGFR, other tyrosine kinase receptors have been reported to be overexpressed in basal-like breast carcinoma: among these prominent druggable targets are c-Kit and the fi broblast growth factor receptor. High levels of c-Kit are preferentially found in BRCA1-associated basal-like tumors; of note, c-Kit mRNA expression appears to be already twofold higher in preneoplastic BRCA1 mutation-associated breast tissue versus non-BRCA1/2 breast tissue, suggesting that c-Kit upregulation may be an early event in BRCA1-driven tumorigenesis [36]. Fibroblast growth factor receptor has been shown to be amplifi ed at the genomic level in two BLBC cell lines; both lines undergo apoptosis following pharmacologic or RNA interferencemediated inactivation of the kinase [54].

Conclusions
Some of the genes described as belonging to the diff erent subtypes of breast cancer have been reported to play important roles in the defi nition of a specifi c cell lineage in normal mammary development and to be deregulated in the tumors that recapitulate the characteristics of that specifi c lineage. For example, the transcription factor GATA3 mediates luminal diff erentiation in gland development and GATA3 defi ciency leads to a block in luminal terminal diff erentiation, with an expansion of the progenitor compartment [34,77]. Consistently, in the tumor counterpart, GATA3 is highly expressed in the luminal subtypes [27,78].
When applying this line of thinking to the HGF/Met system, one could speculate that the correlation between Met expression and basal markers refl ects a precise Met function in physiological gland development; namely, in the defi nition of a poorly diff erentiated basal compart ment and/or in the negative regulation of luminal terminal diff erentiation. Future work is needed to address the role of Met in mammary lineage determination and to analyze whether Met activation can trigger a genetic/molecular program that dictates commitment to one specifi c mammary subpopulation with respect to the others.
While the association between high Met expression and human basal cancers is now well defi ned, the causative role for Met in the onset and/or maintenance of BLBCs is less clear: mice in which active forms of Met are specifi cally expressed in the mammary epithelium develop breast carcinomas with basal-like features, but they are also prone to tumors with phenotypic and molecular characteristics other than those of BLBCs [52,53]. To tackle this issue at the clinical level, it will be interesting to explore whether targeting of Met in basallike cancer will have therapeutic value. Several anti-Met antibodies and small-molecule Met inhibitors have been recently developed, and many of them are now being tested in phase 1 and phase 2 clinical trials [79][80][81] ( Table 2). Th ese agents will probably prove useful in combination with other therapies, including EGFR, c-Kit, and fi broblast growth factor receptor inhibitors. At present, the availability of mouse models that develop Met-driven basal-like breast tumors provides a useful experimental platform to assay the effi cacy of Met inhibition in the preclinical setting and to guide future intervention in human patients.