Molecular Interventions 2:360-362 (2002)
© 2002 American Society of Pharmacology and Experimental Therapeutics
What is the Value of Measuring MTA-1s in Breast Cancer?
Guojun Cheng,
Otabek Imamov,
Yoko Omoto,
Margaret Warner and
Jan-Åke Gustafsson
Department of Medical Nutrition and Department of Biosciences, Karolinska Institute; NOVUM, Huddinge University Hospital, Huddinge, Sweden
SUMMARY
The presence or absence of estrogen receptor (ER) expression in tumor cells affects prognosis and guides treatment choices. Kumar et al. suggest that a shortened form of the metastatic tumor antigen 1 (MTA1s) acts to sequester the estrogen receptor (ER) in the cytoplasm, inhibiting its ability to transactivate specific genes and, presumably, adding to the ER’s ability to transduce non-genomic (cytoplasmic) signaling mechanisms. However, if the cancer is negative for ER
in the nucleus, but is positive for ER in the cytoplasm, how does this sequestration affect the treatment of the patient or our understanding of the disease process? Cheng et al. caution that these results must be interpreted carefully with regard to what is known about estrogen-dependent and -independent tumor growth and chemotherapeutic strategies to destroy them.
Described in the recent paper by Kumar et al. is an elegant study of metastatic tumor antigen-1 (MTA-1) and its splice variant (MTA-1s) in adenocarcinoma of the breast (1) . Perhaps the study itself was not intended to answer questions of clinical value, but instead to investigate possible mechanisms of cytosolic retention of ER in breast cancer cells. Nevertheless, the background information cited in the paper, namely, that nuclear ER is a good prognostic marker for breast cancer, and that high expression of MTA1 is associated with invasiveness, does set the tone and raises expectations that issues related to breast cancer will be addressed. The conclusion of the study is that MTA-1s is expressed in the cytoplasm of ER -negative breast cancers—that is, cancers that do not express any nuclear-localized ER —and that MTA-1s sequesters ER in the cytoplasmic compartment thus preventing its transcriptional activity.
In a previous study, Kumar et al. showed that MTA-1 is a potent corepressor of estrogen receptor element- (ERE)-dependent gene transcription, because it blocks the ability of estradiol to stimulate ER-mediated transcription. MTA-1 also directly interacts with histone deacetylase-1 and -2 and with the activation domain of ER (2) . Furthermore, overexpression of MTA1 in breast cancer cells results in increased invasiveness and anchorage-independent growth. In other words, ER-mediated transcription is blocked by both MTA1 and the MTA splice variant, MTA-1s.
How does this information help us to understand breast cancer and its treatment?
It is known that the presence of nuclear ER in breast cancer (Figure 1
) is a good prognostic indicator of whether a patient will respond to antiestrogen therapy. (A good response being that, upon tamoxifen treatment, the patient will be in remission for five years or more.) Tamoxifen is an antiestrogen used clinically to block the actions of estrogen. It binds to the ligand-binding site in ERs and prevents the binding of estradiol. When tamoxifen is bound to ER, the receptor assumes a conformation that does not permit its interaction with coactivator proteins, and the receptor is transcriptionally inactive. Clinicians are also very clear on one point: if a particular breast cancer has high ER expression, the prognosis is much better than if the cancer is ER negative, whether or not the patient is treated with tamoxifen. It appears that an ER -expressing cancer is in a better-differentiated, less malignant state and that estrogen is still an important growth factor, as it is in normal breast tissue. Antiestrogens can be used successfully to inhibit growth of such tumors. In an ER -negative cancer, growth is regulated by factors other than estrogen.
If a splice variant of MTA1 is expressed in the cytosol and if it sequesters ER into this compartment, ER would be transcriptionally inactive. Would this not be similar to blocking ER action with an antiestrogen? If the cancer cells have ER in their cytoplasm but not in their nuclei, the presence of MTA-1s might account for the sequestration of ER in the cytoplasm. If MTA-1s is expressed in cancers that do not express ER in the nucleus, does this mean that it is a marker for less well-differentiated cancer? Or does it mean that a well-differentiated cancer can appear to be ER -negative because its ER is sequestered in the cytoplasm? Alternatively, does it mean that this cancer has already escaped growth regulation by estrogen?
Two factors have to be considered before we focus too much attention on the clinical usefulness of MTA-1s. The first is that all proteins with LXXLL motifs—and there are hundreds of these—will compete with ER for binding to MTA-1s. ER would have to be sequestered in the cytoplasm by MTA-1s, in order for MTA-1s to exert a physiologically important influence on ER function in breast cancer cells. The conundrum is that the expression level of ER is very low in cells, much lower than those of the glucocorticoid receptor (GR), ER , or progesterone receptor (PR). Thus, we might expect many other LXXLL-containing proteins to successfully compete with ER for binding to MTA-1s in the cytoplasm. The second factor, which must be included in the overall equation, is the expression of ERß (Figure 2), which was mentioned in the Kumar study. In many breast cancers, the amounts of expressed ERß are higher than that of ER and would compete with ER for available cytosolic MTA-1s. Yet, it is clear that responsiveness of breast cancer to tamoxifen is related to expression of ER and not ERß . Does this mean that, in MTA-1s-expressing cancers, expression of ERß might allow more ER to remain in the nucleus and thus restore responsiveness to tamoxifen?
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Figure 2. ERß expression. (Inset) ERß is widely expressed in breast cancer, but the clinical significance of this is not clear. This image is an example of invasive ductal cancer of the breast stained with an ERß -specific polyclonal antibody (Upstate Biotech).
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In order to put all of these questions into perspective, we need to know whether accumulation of MTA-1s in cytosol is a primary event in the development of invasiveness and resistance to tamoxifen, or whether it is one of several changes that occurs as cells continue to replicate and become more malignant. A large number of metastasis-associated genes have been identified (3) . Toh et al. originally found that the MTA gene in this study was more highly expressed in metastatic than in nonmetastatic cell lines (4) . This gene is expressed in all normal tissue and is thought to be involved in cell proliferation. It is also expressed in gastrointestinal and esophageal cancers (5, 6) . If expression of MTA-1s is the key factor in sequestration of ER in cytosol, and this process switches on a more invasive phenotype, then the clinical value of the Kumar et al. (1) study becomes clear. It might be possible that by blocking the activity of MTA-1s in breast cancer cells, we could prevent the sequestration of ER in the cytoplasm and halt the progress of the cancer phenotype toward more a malignant form. In this case, clinicians would have a new contribution to the arsenal of adjuvant treatment of breast cancer.
It might be too early to judge the clinical significance of MTA -1s expression. In the paper by Kumar et al. (1) , there are thirty-one breast cancer samples. Although most of the ER -negative cancer samples have higher levels of MTA-1s as compared to ER -positive samples, there are three ER -negative samples with lower amounts of MTA-1s, and the MTA-1s levels in ER -positive samples vary widely. No correlations were made between ER expression and tumor differentiation or menopausal status of patients, both of which do influence ER status of tumors. Perhaps, in the future, we can look forward to a random, blinded study where the expression of MTA-1s in human cancer samples is compared with invasiveness and state of differentiation of each tumor. In addition, in order to illustrate that it is the ER -negative cells that express MTAs, colocalization of MTAs and ER in cancers is necessary, because in ER -positive samples, there are many cells that do not express ER .
At present, there is no evidence that the measurement of MTA-1s will act as a prognostic marker or as an index for antiestrogen treatment. But it is reassuring to know that these MTA-1s positive patients, who would not normally be treated with tamoxifen, should not be treated with tamoxifen.
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Jan-Åke Gustafsson, MD, PhD, received his training in biochemistry at the Karolinska
Institute. He is presently a Professor of Medical Nutrition and Director of Center for BioTechnology, Karolinska Institute, Novum, Huddinge, Sweden. Please address correspondence to J-ÅG. Email jan-ake.gustafsson{at}mednut.ki.se
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Otabek Imamov, MD, received his training in urology in Russia and is, at present, a Graduate Student at the Department of Medical Nutrition, Karolinska Institute, Novum, Huddinge, Sweden.
Yoko Omoto, MD, PhD, trained in Japan with an interest in hormone-related cancers. She is presently a postdoctoral fellow at the Department of Medical Nutrition, Karolinska Institute, Novum, Huddinge, Sweden.
Margaret Warner, PhD, received her training in pharmacology at McGill University. She is presently a Research Scientist at the Department of Bioscience, Karolinska Institute, Novum, Huddinge, Sweden.
Guojun Cheng, MD, PhD, received his training in gynecology in China, and is a postdoctoral fellow in the Department of Medical Nutrition, Karolinska Institute, Novum, Huddinge, Sweden.
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References
- Kumar, R., Wang, R.A., Mazumdar, A. et al. A naturally occurring MTA1 variant sequesters oestrogen receptor- in the cytoplasm. Nature 418 , 654–657 (2002).[CrossRef][Medline]
- Mazumdar, A., Wang, R.A., Mishra, S.K., Adam, L., Bagheri-Yarmand, R., Mandal, M., Vadlamudi, R.K., and Kumar, R. Transcriptional repression of oestrogen receptor by metastasis-associated protein 1 corepressor. Nat. Cell Biol. 3 , 30–37 (2001).[CrossRef][Medline]
- Nishizuka, I., Ishikawa, T., Hamaguchi, Y. et al. Analysis of gene expression involved in brain metastasis from breast cancer using cDNA microarray. Breast Cancer 9 , 26–32 (2002).[Medline]
- Toh, Y., Pencil, S.D., and Nicolson, G.L. Analysis of the complete sequence of the novel metastasis-associated candidate gene, mta1 , differentially expressed in mammary adenocarcinoma and breast cancer cell lines. Gene 159 , 97–104 (1995).[CrossRef][Medline]
- Toh, Y., Oki, E., Oda, S., Tokunaga, E., Ohno, S., Maehara, Y., Nicolson, G. L., and Sugimachi, K. Overexpression of the MTA1 gene in gastrointestinal carcinomas: Correlation with invasion and metastasis. Int. J. Cancer 74 , 459–463 (1997).[CrossRef][Medline]
- Yasuda, M., Kuwano, H., Watanabe, M., Toh, Y., Ohno, S., and Sugimachi, K. p53 expression in squamous dysplasia associated with carcinoma of the oesophagus: Evidence for field carcinogenesis. Br. J. Cancer 83 , 1033–1038 (2000).[Medline]
Copyright © 2002 by the American Society for Pharmacology and Experimental Therapeutics.
