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Receptor-selective retinoids inhibit the growth of normal and malignant breast cells by inducing G1 cell cycle blockade

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Summary

Despite advances in treatment, breast cancer continues to be the second leading cause of cancer mortality in women. Statistics suggest that while focus on treatment should continue, chemopreventive approaches should also be pursued. Previous studies have demonstrated that naturally occurring retinoids such as 9-cis retinoic acid (9cRA) can prevent breast cancer in animal models. However, these studies have also shown that these compounds are too toxic for general use. Work from our laboratory showed that an RXR-selective retinoid LGD1069 prevented tumor development in animal models of cancer with reduced toxicity as compared to an RAR-selective retinoid TTNPB. In the present study, we investigated the mechanisms by which receptor-selective retinoids inhibit the growth of normal and malignant breast cells. Our results demonstrate that the synthetic retinoids tested are as effective as 9cRA in suppressing the growth of normal human mammary epithelial cells (HMECs) and estrogen receptor-positive (ER-positive) breast cancer cells. Although the receptor-selective retinoids induce minimal amounts of apoptosis in T47D breast cancer cells, the predominant factor that leads to growth arrest is G1 cell cycle blockade. Our data indicate that this blockade results from the downregulation of Cyclin D1 and Cyclin D3, which in turn causes Rb hypophosphorylation. Non-toxic retinoids that are potent inducers of cell cycle arrest may be particularly useful for the prevention of breast cancer.

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Abbreviations

9cRA:

9-cis retinoic acid

atRA:

all-trans retinoic acid

4-HPR:

N-(4-hydroxyphenyl)retinamide

RAR:

retinoic acid receptor

RXR:

retinoid X receptor

ER:

estrogen receptor

HMEC:

human mammary epithelial cell

QRT-PCR:

quantitative reverse transcriptase polymerase chain reaction

SERMs:

selective estrogen receptor modulators

COX:

cyclooxygenase

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Acknowledgements

We would like to thank Drs. Peter J.A. Davies, Gregory L. Shipley, and Nancy S. Shipley for help with the QRT-PCR assays. We would also like to thank Mr. Corey Speers and Ms. Shirley Pennington for their assistance with the preparation of this manuscript. This work was supported by NIH R01 CA078480, NIH U19 CA086809.

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Correspondence to Powel H. Brown.

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Wu, K., DuPré, E., Kim, H. et al. Receptor-selective retinoids inhibit the growth of normal and malignant breast cells by inducing G1 cell cycle blockade. Breast Cancer Res Treat 96, 147–157 (2006). https://doi.org/10.1007/s10549-005-9071-1

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  • DOI: https://doi.org/10.1007/s10549-005-9071-1

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