Kendall Wu

Role of retinoid receptors in the prevention and treatment of breast cancer

Retinoids are vitamin A-related compounds thathave been found to prevent cancer in animals and humans.In this review, we discuss the role of retinoids andtheir receptors in the treatment and prevention of breast cancer. The retinoid receptors areexpressed in normal and malignant breast cells, and arecritical for normal development. In breast cells, whenbound by retinoid hormones, these proteins regulate proliferation, apoptosis, and differentiation.The mechanism by which retinoids inhibit breast cellgrowth has not been completely elucidated, however,retinoids have been shown to affect multiple signal transduction pathways, including IGF-,TGFβ-, and AP-1-dependent pathways. Retinoids havealso been shown to suppress the growth and prevent thedevelopment of breast cancer in animals. These agents suppress tumorigenesis in carcinogen-treatedrats and in transgenic mice, and inhibit the growth oftransplanted breast tumors. These promising preclinicalresults have provided the rationale to test retinoids in clinical trials for the treatment andprevention of breast cancer. Several retinoids,including all trans retinoic acid and9-cis retinoic acid, have been shown to havemodest activity in the treatment of breast cancer, and theseagents are now in clinical trials in combination withcytotoxic agents and anti-estrogens. Another retinoid,4-HPR, is currently being tested in a human cancer prevention trial. Preliminary results suggestthat 4-HPR may suppress breast cancer development inpremenopausal women. Future clinical trials will focuson testing new synthetic retinoids that have reduced toxicity and enhanced therapeutic andpreventive efficacy.

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

SummaryDespite 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.

Estrogen receptor DNA binding is not required for estrogen-induced breast cell growth

In this study, we determined whether ER DNA binding is necessary for estrogen to stimulate the growth of breast cancer cells. To investigate the requirement of ER DNA binding we expressed either wild-type or a DNA-binding mutant ERalpha in a clone of the MCF-7 breast cancer cell line that no longer expressed endogenous ERalpha. Estrogen did not activate non-genomic kinase cascades in the parental MCF-7 cells or in cells expressing ERalpha mutant. In cells expressing the ERalpha mutant, estrogen did not induce ERE-dependent gene expression but did induce AP-1- and Sp1-dependent gene expression and the cell cycle regulatory genes cyclin D1 and c-myc. However, we demonstrated that estrogen still induced cell proliferation in MCF-7 cells expressing the ERalpha mutant. These results demonstrate that ER DNA binding is not absolutely required for estrogen to induce breast cancer cell growth.