Targeting hormonal and growth factor signaling pathways has proven to be useful in the treatment of breast cancer. In vitro, animal, and epidemiologic evidence provide a rationale for the relevance of the insulin-like growth factor (IGF) system to breast cancer biology. The IGF system has been implicated in promoting mitogenic, metastatic, and antiapoptotic phenotypes in breast cancer. As a consequence of the ability of IGF to promote tumorigenesis, pharmacologic interventions targeting the IGF system are being devised. Such strategies include decreasing ligand production, ligand binding, or receptor activation. In this article, directed anti-IGF strategies and the possible clinical impact of using such therapies for treating breast cancer are discussed.

Insulin-like growth factor (IGF) is a potent mitogen involved in normal growth and development. IGF-I is synthesized in the liver upon stimulation by pituitary-released growth hormone and may act on peripheral tissues after redistribution (1, 2). IGF-I is also a paracrine and autocrine mediator of growth. In addition, IGF-I mediates growth, metastasis, and apoptotic responses in cancer (for a review, see ref. 3). Whereas IGF-I is the primary mediator of linear skeletal growth during puberty, the highly homologous molecule IGF-II also has the ability to stimulate cells.

The type 1 IGF receptor (IGF-1R) is the primary response mediator to the IGF ligands and is expressed in all cell types with the exception of hepatocytes and T lymphocytes (4, 5). The IGF-1R is a crucial component of normal development (6, 7). Mouse embryos lacking IGF-1R have lung, neurologic, skin, and bone defects and are variably viable after birth (6, 8). Besides the role of the IGF-1R in normal development, the IGF-1R has been implicated in malignant progression by studies demonstrating that the IGF pathway is involved in cancer growth, transformation, metastasis, and inhibition of apoptosis (9–12). Furthermore, cells expressing mutant IGF-1R fail to undergo malignant transformation and in vivo tumorigenesis (13, 14).

It has been clearly shown that IGF-I signals through the IGF-1R and that adaptor molecules such as insulin receptor substrate-1 (IRS-1) mediate downstream signaling; IRS-1 is tyrosine phosphorylated after IGF-I binding to the IGF-1R (15). Consequently, downstream signaling pathways such as phosphatidylinositol 3-kinase, mitogen-activated protein kinase, and C-Jun NH2-terminal kinase are activated (15–17). By means of these signaling partners, IRS-1 regulates IGF-I–induced gene expression.

High IRS-1 levels are correlated with worse disease-free survival in a subset of patients with breast cancer (18). In support of this epidemiologic data, the activation of the phosphatidylinositol 3-kinase/Akt pathway by IRS-1 also results in the activation of multiple pathways important in cell survival, effectively inhibiting any proapoptotic stimuli such as cytotoxic chemotherapy (19, 20).

IRS-2, another adaptor protein highly homologous to IRS-1, is associated with the metastatic phenotype. IRS-2 phosphorylation is increased relative to IRS-1 phosphorylation after IGF-I stimulation of cell migration in the highly metastatic LCC6 and MDA-231BO cells (21). Moreover, transfection of cells with an IRS-2 antisense mRNA expression vector resulted in decreased levels of IRS-2 with diminished IGF-mediated motility. Collectively, these studies suggest that the IGF-I induced activation of specific adaptor proteins may account for the different observed phenotypes in breast cancer. These studies implicate IGF-I, IGF-1R, and the IRS proteins as pathways involved in the maintenance of the malignant phenotype.

In addition to being involved in phenotype maintenance, IGF-I also plays a role in malignant transformation. To establish the role of the IGF system in the transformation of breast epithelium, investigators have manipulated IGF-I levels in animals by means of transgenic modulation of growth hormone and IGF-I. Transgenic mice overexpressing growth hormone or IGF-I show increased rates of mammary tumor development (22, 23). However, these animals do not generate mammary tumors as a direct result of the increased levels of local or endocrine IGF-I but require other factors to establish the complete malignant phenotype. It is therefore hypothesized that breast epithelial cell stimulation by IGF-I may prime cells to become transformed by a second event (23). Primate studies also provide support for role of IGF-I in disease progression and development, in which it has been shown that primates treated with growth hormone or IGF-I develop mammary hyperplasias (24). To more precisely address breast cancer development, mice that overexpress IGF-I in the mammary gland were used. Under the control of the rat whey acid promoter, 53% of transgenic mice expressing human (des1-3)-IGF-I protein developed mammary adenocarcinomas (22). Mammary tumorigenesis was further enhanced when these mice were crossed with p53 mutants. These transgenic animals showed that elevated serum or local mammary gland IGF-I can promote the development of breast cancer. To address the significance of these levels in animals, liver-specific IGF-I gene deletion animals were created. Liver IGF-I–deficient mice with a 75% reduction in circulating IGF-I levels exhibited a reduction in mammary tumor development (25, 26). Therefore, increases in serum or local IGF-I levels are associated with increased cancer incidence, whereas animals with diminished serum levels display a reduction in tumor formation.

In humans, IGF-I has been implicated in cancer risk in prostate, colorectal, and breast cancer. Serum levels of IGF-I and cancer risk were initially evaluated in a nested case-control study using stored plasma samples from the Physicians' Health Study, which enrolled 14,196 men in 1982 and followed them up over time (27). By the subsequent follow-up period, 520 subjects developed prostate cancer. Of those, 152 subjects had enough plasma available to measure IGF-I, IGF-II, and IGF-binding protein (IGFBP)-3 levels. There was a strong positive correlation between IGF-I levels and prostate cancer risk; men in the highest quartile of plasma IGF-I levels had a 4.3-fold higher risk of developing prostate cancer compared with the men in the lowest quartile. Another prospective case-control study nested in the Physicians Health Study also determined colorectal cancer risk. Ma et al. examined IGF-I, IGF-II, and IGFBP-3 levels from plasma samples based on the hypothesis that men with elevated plasma IGF-I would have an increased risk of colorectal cancer and men with high levels of IGFBP-3 would have a lower risk (28). After controlling for IGFBP-3, age, smoking, and body mass, it was determined that men with elevated IGF-I had an increased risk of colorectal cancer (2.51-fold). In addition, men with higher IGFBP-3 levels had a lower risk (0.28-fold) whereas IGF-II was not associated with colorectal cancer risk. Similarly, a nested case-control study within the prospective Nurses' Health Study revealed an association between IGF-I plasma concentrations and premenopausal breast cancer risk (<50 years; 2.33-fold). For women with elevated IGF-I levels who were <50 years of age when blood was drawn, risk of subsequent breast cancer (either pre- or postmenopausal) was even greater (4.58-fold; ref. 29).

Many other studies have also evaluated IGF-I serum levels and cancer risk. Of these studies, several have reported differing conclusions about IGF levels and cancer risk; however, the majority of evidence reported supports the role of high IGF-I levels in increased cancer risk (30). These correlative studies, however, can only provide supportive evidence that IGF-I levels could increase the risk of developing cancer and cannot establish causation.

IGF-I levels are not the only IGF pathway component shown to be clinically associated with breast cancer. IGF-1R levels are elevated in essentially all breast cancer cell lines and often in fresh tumor biopsies (31). Whereas IGF-1R protein levels are elevated in tumor tissues compared with normal epithelium, there is evidence that IGF-1R mRNA is higher in normal tissue than in tumor samples (32), suggesting that posttranslational mechanisms of IGF-1R expression may be important in breast cancer. Furthermore, IGF-1R levels positively correlate with estrogen receptor-α expression (33, 34). Similar to estrogen receptor-α (35), higher levels of IGF-1R breast cancer correlate with better prognosis. It has been shown that estrogen and IGF-I action are linked; tamoxifen treatment of MCF-7 cells overexpressing the IGF-1R results in a reduction in IGF-1R and IRS-1 tyrosine phosphorylation (36).

Whereas increased IGF-1R levels alone do not prove that this signaling pathway is activated, it has been shown that tumor IGF-1R autophosphorylation and kinase activity are elevated approximately 40-fold over normal mammary epithelium. Furthermore, expression of IRS-1 is correlated with estrogen receptor-α expression and associated with worse disease-free survival in a subset of breast cancer (18, 37). Although this may seem contradictory, it is possible that an intact IGF-1R signaling pathway identifies a subset of estrogen receptor-α–positive tumors with a more aggressive biology. Thus, inhibition of both IGF-1R and estrogen receptor-α signaling may be effective combination therapy.

Inhibition of the IGF pathway may also be applicable in cancer prevention. As the above-mentioned studies suggest, the IGF pathway may be involved in disease development as well as progression, and elevated serum IGF-I levels increase the risk of cancer. Therefore, manipulating IGF-I levels may lead to a decreased cancer risk and could have an important clinical impact.

Existing targeted therapies for breast cancer are based on targeting receptors of disease-promoting pathways. This approach has proven quite effective in the clinical setting for the treatment of ER, HER2 (ErbB2), and more recently, epidermal growth factor receptor (ErbB1) expressing malignancies (35, 38 39). Manipulation of the IGF system, however, has followed a varied approach due to some limitations, to be discussed below, presented by the system. The involvement of several components of the IGF system in disease development and progression offer multiple targets for therapy and provide numerous opportunities for target specificity. Approaches to targeting the IGF system include the reduction and neutralization of IGF ligand, down-regulation and antagonism of IGF-1R, and development of IGF-independent antagonistic strategies.

Lowering Circulating Levels of IGF-I

Because IGF-I and estrogen action are linked, targeting both pathways concurrently for the treatment of breast cancer may prove more efficacious than targeting either pathway alone. In an attempt to diminish IGF-I levels and improve tamoxifen efficacy in patients with breast cancer, Ingle et al. studied the ability of a somatostatin analogue, octreotide, to increase the therapeutic efficacy of tamoxifen (40). Although this trial did not achieve any additional clinical benefit for the administration of octreotide with tamoxifen, it is possible that octreotide did not abrogate IGF-I levels. A more potent growth hormone antagonist, pegvisomant, is being tested in this setting, in which preliminary reports of several model systems suggest that pegvisomant could have antitumor effects (41, 42).

Although a reduction in endocrine IGF-I may be of benefit in breast cancer prevention or treatment, this strategy does not affect IGF-II serum levels. Because adult humans have substantial levels of IGF-II, inhibition of both IGF-I and IGF-II may be necessary. Therefore, direct inhibitors have been developed, ranging from the application of endogenous IGFBP to neutralize both ligands to strategies designed to block receptor activation (dominant negative IGF-1R, IGF-1R antisense, IGF-1R antibodies, and IGF-1R tyrosine kinase inhibitors).

Neutralization of IGF Ligands

The use of endogenous inhibitors of the IGF system to modulate IGF action is proving to be a logical approach. IGFBPs function to transport and modulate IGF action. Whereas the production of IGFBPs in breast cancer cells has been reported, IGFBP levels vary depending on ER status as a function of estrogen-regulated expression (43–45). This suggests that breast cancer cells modulate their own IGF-I signal to promote specific malignant phenotypes. Taking advantage of this regulatory mechanism, select IGFBPs are under evaluation for therapeutic purposes. IGFBP-1 has been shown to inhibit IGF-I action and reduce IGF-induced migration and cell proliferation. IGFBP-1 has also been shown to abrogate estradiol-stimulated growth in MCF-7 cells and to function as an inhibitor of breast cancer migration independent of IGF-I presence in vitro(46, 47). In addition to ligand sequestration, IGFBP-1 seems to affect integrin binding and intracellular signaling modulation independent of IGF ligand (48). As a modulator of IGF action, IGFBP-1 inhibits the IGF pathway from sites upstream of receptor activation. By functioning at a level above the IGF-1R, IGFBP-1 circumvents complications faced by other strategies. In addition, IGFBP-1 also inhibits cancer cell motility via its integrin-binding domain (47). Enhancement of the pharmacokinetic properties of IGFBPs may be important in developing an effective anti-IGF agent. For example, polyethylene glycol–conjugated IGFBP-1 inhibits tumor growth of breast cancer cells in vivo and improves the pharmacokinetic profile of IGFBP-1 (49).

Other IGFBPs have also been suggested to have a role in cancer regulation. For example, Oh et al. showed a regulatory role for IGFBP-3 in breast cancer by means of membrane-bound IGFBP-3 release upon IGF exposure and IGF-independent action of IGFBP-3 on monolayer growth of Hs578T breast cancer cells (50, 51). Transcriptional up-regulation of IGFBP-3 by means of exposure to endogenous and exogenous compounds has also been observed, in which differing functional activities of IGFBP-3 have been described (52, 53). Yu et al. have shown that exogenous IGFBP-3 enhanced the antitumor properties of paclitaxel (54). Although it is still unclear whether IGFBP species can be used to inhibit breast cancer, it is evident that harnessing such endogenous regulators could have benefits over other strategies in breast cancer treatment by providing dual mechanisms of inhibition (i.e., proapoptotic and anti-IGF).

Inhibition of IGF-1R Function

IGF-1R antisense oligonucleotides have been used to down-regulate expression. The transfection of IGF-1R antisense oligonucleotides effectively reduces IGF-1R mRNA, protein, and IGF-induced gene transcription and cell growth (55, 56). Recent reports on the use of IGF-1R antisense in the clinical setting to treat patients with cancer have been positive (57, 58).

The concept of ligand sequestration has been extended to a dominant-negative form of the IGF-1R. Because the IGF-1R binds ligand, a nonfunctional receptor would compete for free ligand and inhibit IGF action (59). The dominant-negative constructs have been widely used to evaluate receptor function. Reiss et al. (59) described such a dominant-negative nonfunctional receptor that also lacks the wild-type transmembrane insertion sequence, resulting in a secreted receptor. The dominant-negative IGF-1R construct has been shown to inhibit the malignant phenotype in breast cancer (13, 60). Lee et al. described a recombinant adenovirus expressing a transmembrane and a soluble dominant-negative, both of which inhibit IGF-induced Akt activation, cell proliferation, and colony formation in vitro and produce a reduction in tumor size in vivo(61).

Another promising approach to targeting the IGF pathway is the use of selective antibodies to neutralize the ligand/receptor interaction. The development of monoclonal antibodies to the IGF-1R has proven quite effective in inhibiting IGF-I action, and these antibodies exhibit antitumor effects in several cancer settings (62–64). These antibodies initiate IGF-1R internalization, effectively down-regulating receptor levels from the cell surface. One monoclonal antibody, αIR-3, was shown to effectively inhibit IGF-I–mediated growth of ER-positive and ER-negative cell lines in vivo but was unable to inhibit estrogen-stimulated DNA synthesis or cell proliferation; αIR-3 exhibited antitumor effects in MDA-231 cells but not in MCF-7 cells (63, 65). More recently, a single-chain antibody has been described that is capable of inhibiting MCF-7 xenograft tumor growth (66). However, agonistic activity has been reported with both of these antibodies, independent of their ability to down-regulate receptor levels (66, 67). Despite the initial activation of IGF-1R biochemical activity, the subsequent down-regulation of IGF-1R by monoclonal antibodies could render cells refractory to further IGF-I stimulation. Antagonistic monoclonal antibodies have also been reported and have been shown to reduce receptor and downstream signaling activation as well as IGF-induced cell proliferation and tumor growth (68, 69).

Because the IGF-1R is a tyrosine kinase, small molecule inhibitors of this activity are, in theory, logical therapeutics for the inhibition of IGF action. Inhibition of IGF-I induced receptor autophosphorylation would inhibit downstream adaptor and signaling pathway activation. Tyrosine kinase inhibitors such as the tyrophostins, AEW541, and similar compounds inhibit IGF-1R biochemical activation and abrogate breast cancer cell growth (70–72). Whereas such molecules may be directed toward the IGF-1R, most of these inhibitors have fundamental drawbacks (70, 73).

Although strategies devised to inhibit mitogenic systems are based on specifically targeting their respective receptors, this method may be difficult for the development of anti-IGF therapeutics. Because the IGF-1R shares 84% amino acid homology with the intracellular β chain tyrosine kinase and 46% to 67% sequence identity with the extracellular α chain of the insulin receptor (IR), IGF-1R inhibitor specificity is limited (74, 75). In the context of breast cancer treatment, adjuvant therapy with nonspecific IGF-1R inhibitors may need to be administered in a chronic fashion, potentially resulting in a simultaneous inhibition of the IR. Even if an IGF-1R–specific method were devised, this method may not completely negate IGF-stimulated activity because IGFs also signal through multiple receptors (IR, IGF-IIR, IR/IGF-1R hybrid). Thus, inhibition of IGF-1R, and not IR, with a specific tyrophostin could be difficult. Moreover, in cancer cells, it is possible that the IR activates biologically relevant signaling pathways (76). It is not clear if specificity for IGF-1R inhibition is desired; if IR plays an important role in breast cancer biology, then simultaneous inhibition of both receptors could be required. It will be challenging to develop a small molecule inhibitor of IGF-1R that inhibits only tumor IGF-1R and IR isoforms without inhibiting host IR.

The development of anti-IGF strategies has helped establish the relevance of the IGF pathway in model systems. Manipulation of IGF action would also prove beneficial in combination with present cytotoxic treatments. These advances in breast cancer treatment have immense potential for improving the survival of a substantial patient population and will need to be evaluated in the clinical setting.

Clinical trials will need to be conducted to prove that these anti-IGF strategies have any relevance to human disease. Current approaches to establishing cancer therapeutics are limited in their capacity for identifying observable response phenotypes. Phase II clinical trials depend on change in tumor size as a measure of therapeutic success. Although it is important to evaluate tumor growth and reduction in tumor size due to apoptosis, this method of therapeutic response evaluation fails to identify effects exerted on tumor metastatic capability. In animal model systems, it is clear that the ability of IGF-1R to enhance tumor metastasis may be completely independent of tumor growth (77). Because these phenotypes are certainly regulated by signal transduction pathways activated by IGF-1R, correlating IGF pathway components with specific phenotypes may assist in identifying appropriate patients for phase II studies.

Whereas primary tumor growth needs to be treated aggressively, tumor metastases to secondary tumor sites present greater difficulty for treatment and are often the primary cause of patient morbidity and mortality. As such, the identification of factors that promote tumor metastasis can provide insight into disease management. As mentioned above, the IGF pathway is intimately involved in breast cancer cell migration. Dominant-negative IGF-1R expression in metastatic MDA-MD-435 breast cancer cells inhibited metastasis (77). Some evidence suggests that specific IRS proteins such as IRS-2 are capable of transducing IGF-migratory signals in breast cancer cells. Furthermore, it has been reported that several components of the IGF system can associate with integrins, cell adhesion receptors involved in cell migration, survival, and growth (78, 79).

Expression of IGF-1R is clearly necessary for IGF-stimulated tumor growth. Beyond this, engagement of specific pathways may have important implications for the interpretation of clinical trial results. Phase II clinical trials measure tumor regression as the key end point. Because IGF-1R may affect tumor metastasis without influencing tumor growth, the design of clinical trials does not allow measurement of all potential malignant phenotypes supported by IGF-1R. Moreover, care must be taken to choose specific biomarkers expected to correlate with response. In model systems, expression of IRS-1 in ER-positive breast cancer correlates with a proliferative phenotype. In contrast, IRS-2 levels and integrin expression in ER-negative tumors identify cells that exhibit a metastatic response to IGF-1R activation. Of course, this is obviously too simplistic a formula; some cells display both a proliferative and a motile phenotype in response to IGF-I (80). Therefore, an assessment of IGF-1R, IRS proteins, and other receptors (ERs and integrins) in tumor samples may identify patients with an elevated risk of metastatic and proliferative disease. Establishing IGF system tumor expression levels may be predictive of tumor phenotypes and give clearer indications of which therapeutics are logically better indicated.

The IGF system has important implications in the treatment of breast cancer. The expression of IGF components has been linked to malignant transformation and disease progression, suggesting that this system may be an effective target for breast cancer therapy. The development of targeted therapeutics to growth factor systems has established their roles as mitogenic pathways that contribute to disease. Whereas most targeted therapies have been developed as receptor-directed inhibitors, the IGF system possesses complications in this regard. Therefore, a rational drug design strategy to target multiple levels of IGF action has been undertaken. Notably, the use of IGFBPs may prove quite effective by inhibiting multiple paths, whereas antibodies and receptor tyrosine kinase inhibitors are also promising strategies with preliminary data showing disease inhibition. The development of anti-IGF strategies should also prove quite helpful in targeting disease regulated by other mitogenic pathways, especially because the IGF pathway may cross-talk with a variety of growth regulatory systems. Furthermore, anti-IGF strategies may also be quite efficacious for the prevention of breast cancer in a subset of patients who have elevated serum IGF levels and are at increased risk for breast cancer. With further examination of the effects seen with these strategies, targeted design IGF system modulators will hopefully translate into treatments for breast cancer.

Dr. Kent Osborne: How would you propose studying, clinically, an antimetastatic agent like this, particularly early on?

Dr. Douglas Yee: I don't have an answer to that. I think this issue has been bothering the angiogenesis researchers as well, in that it's a very difficult clinical trial design. I will comment that this motility in metastasis phenotype is seen in other diseases besides breast cancer. We have been working with collaborators who find it in melanoma and mesothelioma, and in some respects the antimetastasis phenotype is easier to detect in those two diseases. Certainly, for a high-risk melanoma, putting somebody on an investigational agent makes some level of sense. In breast cancer I think it will be very difficult.

Dr. Stephen Johnston: The MMPs [matrix metalloproteinases] went into a postinduction chemotherapy maintenance role. They have been uniformly disappointing, but I think that might be a possible clinical trial scenario. So it is either a group of patients that develop local regional recurrences or are at very high risk up front, which essentially suggests a trial as adjuvant therapy in a high-risk node-positive population.

Dr. Carlos Arteaga: We see very similar things with TGF-β inhibitors, in that we don't see an obvious effect on the primary tumor, but we see a very profound antimetastatic effect. However, when we look at the primary tumors we see some evidence of activity as indicated by increased apoptosis as well as a different histology. Have you looked at the primary tumors in your studies?

Dr. Yee: We send our animals over to our veterinary pathology colleagues and they actually don't see any difference in the tumor. Now, we did look at the buffy coats of these animals and those that have dominant negative receptor or are treated with anti–IGF-1R antibody don't actually have circulating tumor cells. So we're not sure what phenotype is being regulated here: it is either invasion in the vasculature or survival in the vasculature. I'm guessing it is going to be survival in the vasculature and that's one of the things that we want to figure out. So, coming back to what should we measure, and how much faith you put in circulating tumor cells as being a biological measure of risk recurrence. It's certainly not good to have circulating tumor cells, and if that's the phenotype you take out, that could be meaningful.

Dr. Arteaga: Well, you know, it is becoming clear that if you compare different transgenic cancer models, all of them with different metastatic rates, the efflux of tumors cells using intravital microscopy is pretty much the same. What is different is their ability to survive in the circulation and then extravasate and set up housekeeping conditions in distal organs.

Dr. Osborne: Were the mice sick? Did they get ketotic?

Dr. Yee: We have not been able to show any change in simple glucose measurement. The Novartis group have actually showed that the animals bumped up their insulin levels to maintain normoglycemia. In other words, treatment induced the metabolic syndrome in that they are hyperinsulinemic, but not hyperglycemic. Those experiments were done over a fairly short period of time and so we don't know about long-term effects.

Dr. Osborne: If it is mild glucose intolerance, it may be perfectly manageable in people.

Dr. Yee: That's right. Now, with the antibodies, I'm not aware that anybody has made a mouse IGF receptor monoclonal antibody to detect mouse toxicity. I think that the next level would be studies in other species, but I don't know how reactive these monoclonals are against primate IGF receptor. So it's going to take some engineering to do the toxicology studies.

Dr. Richard Santen: In regard to the signaling pathways, we have observed that the estrogen receptor co-opts the IGF1 pathway through a nongenomic effect by binding to the IGF-1R [Song RX et al. Proc Natl Acad Sci U S A 2004;101:2076–81]. If that were operative in your system, I would expect that estrogen stimulation of tumor growth could be blocked by the IGF-1R antibodies or tyrosine kinase inhibitors. Have you looked at that to see whether there is a link between estrogen stimulation and utilization of the IGF-1R?

Dr. Yee: We have not looked at it in the nongenomic or extranuclear model, but the animal experiments show that you inhibit estrogen-stimulated growth at some level, because you have to give the animals estrogen pellets to get the tumors to grow at all. In vitro it goes both ways: if you inhibit estrogen receptors, you inhibit IGF signaling because all the components are down-regulated and vice versa. If you inhibit an IGF receptor, the estrogen receptor doesn't function quite as well, but we've never really looked very closely at whether or not it's a nuclear or an extranuclear event.

Presented at the 4th International Conference on Recent Advances and Future Directions in Endocrine Manipulation of Breast Cancer, July 21-22, 2004, Cambridge, Massachusetts.

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