This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Dawson, M. I. Articles by Fontana, J. A. Search for Related Content PubMed PubMed Citation Articles by Dawson, M. I. Articles by Fontana, J. A.

Correlation of Retinoid Binding Affinity to Retinoic Acid Receptor with Retinoid Inhibition of Growth of Estrogen Receptor-positive MCF-7 Mammary Carcinoma Cells¹

Life Sciences Division, SRI International, Menlo Park, California 94025 [M. I. D., W. C., P. P., L. J., P. D. H., C. K. R.]; Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts 02118 [T. C. Q.]; Department of Biochemistry and Molecular Biology, Marshall University School of Medicine, Huntington, West Virginia 25755 [R. M. N.]; Cancer Center, La Jolla Cancer Research Foundation, La Jolla, California 92037 [A. L., K. R. E., X. Z.]; CIRD Galderma, 06902 Sophia Antipolis Cedex, France [B. S.]; and Department of Medicine, Division of Oncology and Cancer Center, University of Maryland, School of Medicine and the Veterans Administration Medical Center, Baltimore, Maryland 21201 [J. A. F.]

Both anchorage-dependent growth and anchorage-independent growth of the estrogen receptor-positive mammary carcinoma cell line MCF-7 are inhibited by all-trans-retinoic acid. This cell line has nuclear retinoic acid receptors (RARs) and . The natural retinoids all-trans-retinoic acid and 9-cis-retinoic acid and a series of 12 conformationally restricted retinoids, which showed a range of binding selectivities for these receptors and had either agonist or antagonist activity for gene transcriptional activation by the RARs, were evaluated for their abilities to inhibit anchorage-dependent (adherent) and anchorage-independent (clonal) growth of MCF-7 cells. Correlation analyses were performed to relate growth inhibition by these retinoids with their binding affinity to RAR or RAR. Inhibition of anchorage-dependent growth in culture after 7 days of retinoid treatment correlated with binding to RAR (n = 14; P 0.001) and not to RAR (n = 14; P > 0.1). Both the RAR-selective retinoid agonists and the two RAR antagonists that were evaluated inhibited adherent cell growth. The RAR-selective agonists had very low growth inhibitory activity (< 10%) at concentrations as high as 12.5 µM. These results suggest that RAR is the retinoid recepter involved in the inhibition of adherent cell growth by retinoids and that transcriptional activation by this receptor on a RAR response element does not appear to be required for this process to occur. For this series of retinoids, inhibition of anchorage-independent growth after 21 days of retinoid treatment only correlated (n = 12; P 0.005) with binding affinity to RAR for the retinoid agonists, although the RAR-selective retinoids displayed weak activity. The RAR antagonists were very poor inhibitors of growth. These results suggest that activation of gene transcription by RAR appears to be required for inhibition of anchorage-independent growth by retinoids in this estrogen receptor-positive mammary carcinoma cell line.

¹ This research was supported by NIH Grants 1 P01 CA51993 (to M. I. D. and K. R. E.) and 1 R01 CA63335 (to J. A. F.).

² To whom requests for reprints should be addressed, at Bio-Organic Chemistry Lab., Life Sciences Division, SRI International, 333 Ravenswood Avenue, Menlo Park, CA 94025.

Received 4/ 6/95. Accepted 7/27/95.

This article has been cited by other articles:

				P. Germain, P. Chambon, G. Eichele, R. M. Evans, M. A. Lazar, M. Leid, A. R. De Lera, R. Lotan, D. J. Mangelsdorf, and H. Gronemeyer International Union of Pharmacology. LX. Retinoic Acid Receptors Pharmacol. Rev., December 1, 2006; 58(4): 712 - 725. [Abstract] [Full Text] [PDF]

				Y. Zhang, M. I. Dawson, R. Mohammad, A. K. Rishi, L. Farhana, K.-C. Feng, M. Leid, V. Peterson, X.-k. Zhang, M. Edelstein, et al. Induction of apoptosis of human B-CLL and ALL cells by a novel retinoid and its nonretinoidal analog Blood, September 26, 2002; 100(8): 2917 - 2925. [Abstract] [Full Text] [PDF]

				E. F. Farias, A. Arapshian, I. J. Bleiweiss, S. Waxman, A. Zelent, and R. Mira-y-Lopez Retinoic Acid Receptor {alpha}2 Is a Growth Suppressor Epigenetically Silenced In MCF-7 Human Breast Cancer Cells Cell Growth Differ., August 1, 2002; 13(8): 335 - 341. [Abstract] [Full Text] [PDF]

				C. L. Rock and W. Demark-Wahnefried Nutrition and Survival After the Diagnosis of Breast Cancer: A Review of the Evidence J. Clin. Oncol., August 1, 2002; 20(15): 3302 - 3316. [Abstract] [Full Text] [PDF]

				A. S. Budhu and N. Noy Direct Channeling of Retinoic Acid between Cellular Retinoic Acid-Binding Protein II and Retinoic Acid Receptor Sensitizes Mammary Carcinoma Cells to Retinoic Acid-Induced Growth Arrest Mol. Cell. Biol., April 15, 2002; 22(8): 2632 - 2641. [Abstract] [Full Text] [PDF]

				M. I. Dawson, P. D. Hobbs, V. J. Peterson, M. Leid, C. W. Lange, K.-C. Feng, G.-q. Chen, J. Gu, H. Li, S. K. Kolluri, et al. Apoptosis Induction in Cancer Cells by a Novel Analogue of 6-[3-(1-Adamantyl)-4-hydroxyphenyl]-2-naphthalenecarboxylic Acid Lacking Retinoid Receptor Transcriptional Activation Activity Cancer Res., June 1, 2001; 61(12): 4723 - 4730. [Abstract] [Full Text] [PDF]

				K. Fukunaka, T. Saito, K. Wataba, K. Ashihara, E. Ito, and R. Kudo Changes in expression and subcellular localization of nuclear retinoic acid receptors in human endometrial epithelium during the menstrual cycle Mol. Hum. Reprod., May 1, 2001; 7(5): 437 - 446. [Abstract] [Full Text] [PDF]

				P. Prakash, R. M. Russell, and N. I. Krinsky In Vitro Inhibition of Proliferation of Estrogen-Dependent and Estrogen-Independent Human Breast Cancer Cells Treated with Carotenoids or Retinoids J. Nutr., May 1, 2001; 131(5): 1574 - 1580. [Abstract] [Full Text]

				Y. Zhang, A. K. Rishi, M. I. Dawson, R. Tschang, L. Farhana, M. Boyanapalli, U. Reichert, B. Shroot, E. C. Van Buren, and J. A. Fontana S-phase Arrest and Apoptosis Induced in Normal Mammary Epithelial Cells by a Novel Retinoid Cancer Res., April 1, 2000; 60(7): 2025 - 2032. [Abstract] [Full Text]

				Q. Wang, W. Yang, M. S. Uytingco, S. Christakos, and R. Wieder 1,25-Dihydroxyvitamin D3 and All-trans-Retinoic Acid Sensitize Breast Cancer Cells to Chemotherapy-induced Cell Death Cancer Res., April 1, 2000; 60(7): 2040 - 2048. [Abstract] [Full Text]

				R. G. Mehta, E. Williamson, M. K. Patel, and H. P. Koeffler A Ligand of Peroxisome Proliferator-Activated Receptor {gamma}, Retinoids, and Prevention of Preneoplastic Mammary Lesions J Natl Cancer Inst, March 1, 2000; 92(5): 418 - 423. [Abstract] [Full Text] [PDF]

				C. E. Clay, A. M. Namen, G.-i. Atsumi, M. C. Willingham, K. P. High, T. E. Kute, A. J. Trimboli, A. N. Fonteh, P. A. Dawson, and F. H. Chilton Influence of J series prostaglandins on apoptosis and tumorigenesis of breast cancer cells Carcinogenesis, October 1, 1999; 20(10): 1905 - 1911. [Abstract] [Full Text] [PDF]

				C. D. Katsetos, I. Stadnicka, J. C. Boyd, H. Ehya, S. Zheng, C. M. Soprano, H. S. Cooper, A. S. Patchefsky, D. R. Soprano, and K. J. Soprano Cellular Distribution of Retinoic Acid Receptor-{alpha} Protein in Serous Adenocarcinomas of Ovarian, Tubal, and Peritoneal Origin : Comparison with Estrogen Receptor Status Am. J. Pathol., August 1, 1998; 153(2): 469 - 480. [Abstract] [Full Text] [PDF]

				E. Elstner, C. Muller, K. Koshizuka, E. A. Williamson, D. Park, H. Asou, P. Shintaku, J. W. Said, D. Heber, and H. P. Koeffler Ligands for peroxisome proliferator-activated receptorgamma and retinoic acid receptor inhibit growth and induce apoptosis of human breast cancer cells in vitro and in BNX mice PNAS, July 21, 1998; 95(15): 8806 - 8811. [Abstract] [Full Text] [PDF]

				G. Sun, W. Porter, and S. Safe Estrogen-Induced Retinoic Acid Receptor {alpha}1 Gene Expression: Role of Estrogen Receptor-Sp1 Complex Mol. Endocrinol., June 1, 1998; 12(6): 882 - 890. [Abstract] [Full Text]

				J van der Wees, J. Schilthuis, C. Koster, H Diesveld-Schipper, G. Folkers, P. van der Saag, M. Dawson, K Shudo, B van der Burg, and A. Durston Inhibition of retinoic acid receptor-mediated signalling alters positional identity in the developing hindbrain Development, January 2, 1998; 125(3): 545 - 556. [Abstract] [PDF]

				R. A. Spanjaard, M. Ikeda, P. J. Lee, B. Charpentier, W. W. Chin, and T. J. Eberlein Specific Activation of Retinoic Acid Receptors (RARs) and Retinoid X Receptors Reveals a Unique Role for RARgamma in Induction of Differentiation and Apoptosis of S91 Melanoma Cells J. Biol. Chem., July 25, 1997; 272(30): 18990 - 18999. [Abstract] [Full Text] [PDF]

				C. Abbondanza, N. Medici, V. Nigro, V. Rossi, L. Gallo, G. Piluso, A. Belsito, A. Roscigno, P. Bontempo, A. A. Puca, et al. The retinoblastoma-interacting zinc-finger protein RIZ is a downstream effector of estrogen action PNAS, March 28, 2000; 97(7): 3130 - 3135. [Abstract] [Full Text] [PDF]