This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this book Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Simpson, E. R. Articles by Dowsett, M. Search for Related Content PubMed PubMed Citation Articles by Simpson, E. R. Articles by Dowsett, M.

Aromatase and Its Inhibitors: Significance for Breast Cancer Therapy

Evan R. Simpson^* and Mitch Dowsett

^* Prince Henry’s Institute of Medical Research, Monash Medical Centre, Clayton, Victoria 3168, Australia
Department of Biochemistry, Royal Marsden Hospital, London SW3 6JJ, United Kingdom

Endocrine adjuvant therapy for breast cancer in recent years has focussed primarily on the use of tamoxifen to inhibit the action of estrogen in the breast. The use of aromatase inhibitors has found much less favor due to poor efficacy and unsustainable side effects. Now, however, the situation is changing rapidly with the introduction of the so-called phase III inhibitors, which display high affinity and specificity towards aromatase. These compounds have been tested in a number of clinical settings and, almost without exception, are proving to be more effective than tamoxifen. They are being approved as first-line therapy for elderly women with advanced disease. In the future, they may well be used not only to treat young, postmenopausal women with early-onset disease but also in the chemoprevention setting. However, since these compounds inhibit the catalytic activity of aromatase, in principle, they will inhibit estrogen biosynthesis in every tissue location of aromatase, leading to fears of bone loss and possibly loss of cognitive function in these younger women. The concept of tissue-specific inhibition of aromatase expression is made possible by the fact that, in postmenopausal women when the ovaries cease to produce estrogen, estrogen functions primarily as a local paracrine and intracrine factor. Furthermore, due to the unique organization of tissue-specific promoters, regulation in each tissue site of expression is controlled by a unique set of regulatory factors. These factors are potential targets for the design of selective aromatase modulators, which could selectively inhibit aromatase expression in breast with the same efficacy as the phase III inhibitors of activity but leave expression in other local sites such as bone and brain untouched.

This article has been cited by other articles:

				A. Brufsky, W. G. Harker, J. T. Beck, R. Carroll, E. Tan-Chiu, C. Seidler, J. Hohneker, L. Lacerna, S. Petrone, and E. A. Perez Zoledronic Acid Inhibits Adjuvant Letrozole-Induced Bone Loss in Postmenopausal Women With Early Breast Cancer J. Clin. Oncol., March 1, 2007; 25(7): 829 - 836. [Abstract] [Full Text] [PDF]

				A. Hirbe, E. A. Morgan, O. Uluckan, and K. Weilbaecher Skeletal complications of breast cancer therapies. Clin. Cancer Res., October 15, 2006; 12(20): 6309s - 6314s. [Abstract] [Full Text] [PDF]

				A. Kendall and M. Dowsett Novel concepts for the chemoprevention of breast cancer through aromatase inhibition. Endocr. Relat. Cancer, September 1, 2006; 13(3): 827 - 837. [Abstract] [Full Text] [PDF]

				R. Lupu and J. A. Menendez Targeting Fatty Acid Synthase in Breast and Endometrial Cancer: An Alternative to Selective Estrogen Receptor Modulators? Endocrinology, September 1, 2006; 147(9): 4056 - 4066. [Abstract] [Full Text] [PDF]

				B. K. Dunn Hormonal Interventions: From Adjuvant Therapy to Breast Cancer Prevention Am. Assoc. Cancer Res. Educ. Book, April 1, 2005; 2005(1): 185 - 188. [Full Text] [PDF]

				B. K. Dunn, D. L. Wickerham, and L. G. Ford Prevention of Hormone-Related Cancers: Breast Cancer J. Clin. Oncol., January 10, 2005; 23(2): 357 - 367. [Abstract] [Full Text] [PDF]

				J. Brosens, H. Verhoeven, R. Campo, L. Gianaroli, S. Gordts, J. Hazekamp, L. Hagglund, T. Mardesic, E. Varila, J. Zech, et al. High endometrial aromatase P450 mRNA expression is associated with poor IVF outcome Hum. Reprod., February 1, 2004; 19(2): 352 - 356. [Abstract] [Full Text] [PDF]

				V. Paharkova-Vatchkova, R. Maldonado, and S. Kovats Estrogen Preferentially Promotes the Differentiation of CD11c+ CD11bintermediate Dendritic Cells from Bone Marrow Precursors J. Immunol., February 1, 2004; 172(3): 1426 - 1436. [Abstract] [Full Text] [PDF]

				I. E. Smith and M. Dowsett Aromatase Inhibitors in Breast Cancer N. Engl. J. Med., June 12, 2003; 348(24): 2431 - 2442. [Full Text] [PDF]