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The Biology Behind |
Authors' Affiliations: 1 The Breast Center, the 2 Duncan Cancer Center, and the 3 Department of Medicine, Baylor College of Medicine, Houston, Texas
Requests for reprints: Rachel Schiff, Breast Center, Baylor College of Medicine, Room N1230.02, One Baylor Plaza-BCM 600, Houston, TX 77030. Phone: 713-798-1676; Fax: 713-798-6146; E-mail: rschiff{at}bcm.tmc.edu.
In this issue of Clinical Cancer Research, Bayliss et al. (1) report that inhibiting inherent p42/44 mitogen-activated protein kinase (MAPK) activity in estrogen receptor (ER) 
–negative breast cancer established cell lines, and in ex vivo tissue and primary cultures of human ER-negative breast tumors, frequently results in re-expression of ER as well as in recovery of tumor cell responsiveness to antiestrogen treatment. The authors have previously shown that in the ER-positive MCF7 cell line, inducing hyperactive MAPK by genetically engineered up-regulation of growth factor signaling leads to a reversible loss of ER expression (2). These intriguing findings highlight the dynamic and heterogeneous nature of ER status in breast cancer and broaden the therapeutic horizon for patients with ER-negative tumors by suggesting that a subset of this group may benefit from a treatment strategy combining signal transduction inhibitors with endocrine therapy.
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ER and Endocrine Therapy in Breast Cancer |
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 Top ER and Endocrine Therapy... Heterogeneity, Origin, and...Regulatory Mechanisms for ER...Hyperactive GFR Signaling as...Conclusion and Future...References |
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ER is mostly a nuclear receptor that acts as a ligand-dependent transcription factor to regulate genes involved in breast cancer cell proliferation, survival, invasion, and tumor angiogenesis. Besides this classic genomic or nuclear activity of ER, an alternative, rapidly manifested activity of ER, stemming from a fraction of the cellular pool of ER residing in the cytoplasm and/or the membrane, has recently been recognized in breast cancer cells. Through this action, ER can directly or indirectly interact with and up-regulate various growth factor receptor (GFR) tyrosine kinases (e.g., HER1, HER2, and insulin-like growth factor-I receptor) as well as signaling intermediates including membrane proteins, signaling adaptor molecules, and cellular kinases (e.g., caveolin, Shc, MNAR/PELP, and Src; refs. 6–8 and references therein). Conversely, GFR signaling can also modulate and enhance the genomic/nuclear activity of ER. This multilevel bidirectional cross-talk between ER and GFR signaling pathways plays an important role in both acquired and de novo resistance to endocrine therapy in breast cancer (refs. 7, 9–11 and references therein). Recent preclinical and clinical data have further shown that acquired resistance to endocrine therapy is frequently associated with significantly increased levels of HER1, HER2, or other GFR downstream signaling molecules (10, 12, 13) and, occasionally, with a substantial down-regulation of ER (12, 14), and that a combined therapy with HER1/2 inhibitors can significantly improve endocrine therapy outcome (10, 13).
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Heterogeneity, Origin, and Biology of ER-Negative Breast Cancer |
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TopER and Endocrine Therapy...Heterogeneity, Origin, and...Regulatory Mechanisms for ER...Hyperactive GFR Signaling as...Conclusion and Future...References |
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Histologic evidence suggests that over the natural course of breast cancer progression, ER can be lost (16). The rather common phenomenon of apocrine metaplasia of nonmalignant and malignant breast epithelium, which is associated with complete ER loss and up-regulation of the androgen receptor, has also been suggested to be involved in the development of some ER-negative breast cancers (17). The cancer stem cell theory provides another mechanistic explanation for the heterogeneous phenotype of ER status in breast. According to this theory, the molecular nature of the early stem or progenitor cells responsible for the origin of the tumor, and the particular mutations driving carcinogenesis, account for the diverse phenotypes of breast cancer and ER status (18, 19).
Molecular classification of human breast tumors based on their intrinsic global expression patterns also emphasizes the heterogeneous molecular nature and biology of breast cancer in general and of ER-negative tumors in particular. Although constantly being refined, this approach has already corroborated several biological subtypes, including the luminal (A and B groups), basal-like, HER2-positive, and normal breast subtypes (20). Importantly, ER-negative tumors have been found in almost all of these categories, although at different percentages. Recognizing the power of this molecular technology, current efforts are focused on further delineating the subclassifications of ER-negative tumors with the purpose of shedding light on key issues regarding the origin and biology of ER-negative breast cancers and identifying novel pathways and targets to improve our presently limited therapeutic strategies for these tumors.
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Regulatory Mechanisms for ER Loss and the Generation of an ER-Negative Phenotype |
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TopER and Endocrine Therapy...Heterogeneity, Origin, and...Regulatory Mechanisms for ER...Hyperactive GFR Signaling as...Conclusion and Future...References |
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In contrast to the genomic/gene level, ER expression and its loss are clearly controlled at the epigenetic level. Hypermethylation of CpG islands within the ER promoter, as observed in 25% of ER-negative breast cancers, has been repeatedly documented as an epigenetic mechanism to transcriptionally silence the ER gene (25, 26). Because both DNA methyltransferases and histone deacetylases play a crucial role in maintaining the transcriptionally repressed state of genes, inhibitors to these enzymes have been used as a therapeutic strategy for restoring ER expression as well as sensitivity to endocrine therapy in preclinical models of ER-negative breast tumors (ref. 27; Fig. 1 and see later discussion).
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At the protein level, manifold posttranslational modifications, including phosphorylation, acetylation, sumoylation, and ubiquitination, not only modulate the different activities of ER but also affect its stability and turnover, which, under specific circumstances (e.g., hypoxia; ref. 30), may result in a complete loss of ER.
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Hyperactive GFR Signaling as a Molecular Determinant of ER Loss: The Dynamic Nature of ER Status and Clinical Implications |
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TopER and Endocrine Therapy...Heterogeneity, Origin, and...Regulatory Mechanisms for ER...Hyperactive GFR Signaling as...Conclusion and Future...References |
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To further investigate this interaction between GFR signaling and the ER pathway, El-Ashry's group has previously constructed, using the ER-positive MCF7 breast cancer cells, an in vitro model of hyperactivated MAPK signaling by exogenous up-regulation either of the GFRs HER1 and HER2, or of a constitutively active Raf or MAP/extracellular signal-regulated kinase kinase (MEK; ref. 2). These genetically engineered cell lines display estrogen-independent growth as well as resistance to antiestrogen therapy and, somewhat unexpectedly, show a complete loss of ER mRNA and protein, due to both transcriptional repression and enhanced protein degradation (Fig. 1). Yet, this acquired ER-negative phenotype is reversible, and abrogation of the MAPK activity by inhibitors of GFRs or downstream kinases, or by dominant negative constructs, rapidly restores ER expression and activity. Although the mechanisms by which elevated MAPK signaling leads to ER down-regulation are still largely unknown, in a subsequent study, El-Ashry's group highlighted the involvement of the nuclear factor-
B transcription factor in this process (33). Molecular profiles identifying a shared "MAPK signature" between these hyperactive MAPK cell lines and human ER-negative breast cancers further support the clinical relevance of this model and reinforce hyperactive MAPK signaling as an underlying mechanism behind the ER-negative phenotype (34).
In the report published in the current issue, Bayliss et al. (1) go on to investigate whether inhibition of MAPK activity stemming from intrinsic hyperactive upstream signaling in both established and primary cultures of human ER-negative tumors can also restore ER expression and sensitivity to endocrine therapy.
The findings of this study suggest that MAPK blockade can restore ER expression in a subset of ER-negative tumors and reestablish endocrine sensitivity in some of these, thereby supporting the potential role of a combined MAPK inhibition/endocrine therapy in ER-negative breast cancer patients (Fig. 1). In tumors in which sensitivity to endocrine therapy is not restored despite ER reactivation, additional therapy targeting alternative signal transduction pathways may be of value. Finally, because hypermethylation of the ER promoter may interfere with reactivation of the ER gene in a subset of ER-negative tumors, adding histone deacetylase inhibitors or other agents capable of inducing DNA demethylation to inhibitors of MAPK or other signaling transduction intermediates in these cases may be an effective strategy to restore ER expression and consequently response to endocrine therapy (Fig. 1).
Recent intriguing data from a few clinical reports clearly support the above molecular scenario and justify further clinical development of these novel treatment strategies for patients with ER-negative tumors. In a recent report of patients with HER2+/ER– advanced breast cancer treated with trastuzumab, ER reexpression was identified in 3 of 10 patients after 9, 12, and 37 months of therapy, and endocrine treatment with an aromatase inhibitor in two of these patients led to a long-term response for >3 years in one of them (35). Similarly, enhanced ER expression levels were also noted in several patients postneoadjuvant trastuzumab (36). Finally, a recent study focusing on the mechanisms of resistance to the dual HER1/2 tyrosine kinase inhibitor lapatinib in HER2-overexpressing tumors also documented treatment-induced enhancement of ER signaling and/or expression, which in the preclinical setting, was proved to be the escape mechanism underlying the acquired resistance to the anti-HER2 lapatinib therapy (37). A simultaneous inhibition of both the ER pathway by endocrine therapy and HER2 by lapatinib in this model system prevented the development of acquired resistance.
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Conclusion and Future Perspective |
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TopER and Endocrine Therapy...Heterogeneity, Origin, and...Regulatory Mechanisms for ER...Hyperactive GFR Signaling as...Conclusion and Future...References |
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Finally, the multilevel cross-talk between ER and the HER pathway in breast cancer, which includes an inverse correlation of expression and functionality between these two pathways, suggests that sensitivity or resistance to targeted therapies against either of these pathways may rely, at least in part, on reactivation of the other pathway. Thus, a strategy of combining therapies against both pathways might often be superior to treatments targeting only one of these two pathways.
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Footnotes |
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Grant support: A breast cancer Specialized Program of Research Excellence Grant (P50 CA58183) from the National Cancer Institute (R. Schiff) and a postdoctoral grant (S. Lopez-Tarruella) from the Fundacion para la Investigacion Biomedica del Hospital Clinico Universitario San Carlos, Madrid, Spain.
Conflict of interest: R. Schiff received grant support from AstraZeneca and Glaxo Smith Kline.
Received 6/ 7/07; revised 6/19/07; accepted 7/18/07.
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References |
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TopER and Endocrine Therapy...Heterogeneity, Origin, and...Regulatory Mechanisms for ER...Hyperactive GFR Signaling as...Conclusion and Future...References |
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expression in breast cancer cells. Mol Endocrinol 2001;15:1344–59. membrane localization and function. Steroids 2005;70:361–3.[CrossRef][Medline]-positive and estrogen receptor -negative human breast cancer. Breast Cancer Res 2004;6:240–5.[CrossRef][Medline]: regulation by synthesis, modification and degradation. Cell Mol Life Sci 2002;59:821–31.[CrossRef][Medline] (ESR1) gene amplification is frequent in breast cancer. Nat Genet 2007;39:655–60.[CrossRef][Medline] expression in breast cancer. Oncologist 2006;11:1–8. (ER) and represses ER messenger RNA and protein expression in breast cancer cell lines. Mol Endocrinol 2007;21:1132–47. in ZR-75 breast cancer cells. Mol Endocrinol 2002;16:2231–42. down-regulation in breast cancer cells: the role of nuclear factor-B. Mol Endocrinol 2004;18:1396–410.-positive breast cancer cells in vitro induces an in vivo molecular phenotype of estrogen receptor -negative human breast tumors. Cancer Res 2006;66:3903–11. expression and is repressed by the Her-2/neu/phosphatidylinositol 3-kinase/Akt signaling pathway. Mol Cell Biol 2004;24:8681–90.Key Article
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