This Article Full Text Full Text (PDF) CME: Take the course for this article: Biologic Basis of Sequential and Combination Therapies for Hormone-Responsi... eLetters: Submit a response to this article Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services E-mail this article link to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Reprints/Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Pietras, R. J. Search for Related Content PubMed Articles by Pietras, R. J.

Breast Cancer

Biologic Basis of Sequential and Combination Therapies for Hormone-Responsive Breast Cancer

UCLA School of Medicine, Department of Medicine-Hematology/Oncology, Los Angeles, California, USA

Key Words. Estrogen receptors • Growth factors • MAP kinase signaling pathway • Genes, HER-2 • Aromatase inhibitors • Fulvestrant • AKT kinase signaling

Correspondence: Richard J. Pietras, M.D., Ph.D., UCLA School of Medicine, Department of Medicine-Hematology/Oncology, 11-934 Fac-tor Building, 10833 Le Conte Avenue, Los Angeles, California 90095-1678, USA. Telephone: 310-825-9769; Fax: 310-825-6192; e-mail: rpietras{at}ucla.edu

Although pharmacologic therapies that reduce or block estrogen signaling are effective treatments of estrogen receptor (ER)-positive breast cancer, acquired resistance to individual drugs can develop. Furthermore, this approach is ineffective as initial therapy for a subgroup of receptor-positive patients. The mechanisms of drug resistance are not completely understood, but the presence of alternative signaling pathways for activating ER response appears to play a significant role. Cross-talk between signaling pathways can activate ERs when conventional ER pathways are blocked or inactivated. For example, signaling via epidermal growth factor or HER-2 receptors, mitogen-activated protein kinases, phosphatidylinositol 3' kinase/protein kinase B, and vascular endothelial growth factor receptor can lead to estrogen-independent stimulation of ERs and tumor growth. The discovery that alternative pathways are involved in estrogen signaling has prompted development of newer endocrine therapies, such as aromatase inhibitors and pure estrogen antagonists, with distinct mechanisms for interrupting signal transduction. The existence of multiple pathways may explain the effectiveness of follow-up therapy with a different class of endocrine agents after failure of prior endocrine treatment. Because they do not have the partial agonist activity of tamoxifen that is enhanced by the adaptive hypersensitivity process, these alternative endocrine agents may play an increasingly important role in the treatment of ER-positive breast cancer. Although optimal sequencing of these agents has not been determined and is continuing to evolve, current evidence allows rational recommendations to be made. The multiple pathways involved in activating ERs also provide a rationale for combining endocrine and non-endocrine therapies that block different signaling pathways, which may have synergistic and overlapping interactions.

This article has been cited by other articles:

				L. F. Macedo, G. J. Sabnis, O. G. Goloubeva, and A. Brodie Combination of Anastrozole with Fulvestrant in the Intratumoral Aromatase Xenograft Model Cancer Res., May 1, 2008; 68(9): 3516 - 3522. [Abstract] [Full Text] [PDF]

				J. K. Nagpal, S. Nair, D. Chakravarty, R. Rajhans, S. Pothana, D. W. Brann, R. R. Tekmal, and R. K. Vadlamudi Growth Factor Regulation of Estrogen Receptor Coregulator PELP1 Functions via Protein Kinase A Pathway Mol. Cancer Res., May 1, 2008; 6(5): 851 - 861. [Abstract] [Full Text] [PDF]

				R. Rajhans, H. B. Nair, S. S. Nair, V. Cortez, K. Ikuko, N. B. Kirma, D. Zhou, A. E. Holden, D. W Brann, S. Chen, et al. Modulation of in Situ Estrogen Synthesis by Proline-, Glutamic Acid-, and Leucine-Rich Protein-1: Potential Estrogen Receptor Autocrine Signaling Loop in Breast Cancer Cells Mol. Endocrinol., March 1, 2008; 22(3): 649 - 664. [Abstract] [Full Text] [PDF]

				R. J. Pietras and D. C. Marquez-Garban Membrane-Associated Estrogen Receptor Signaling Pathways in Human Cancers Clin. Cancer Res., August 15, 2007; 13(16): 4672 - 4676. [Full Text] [PDF]