The Effect of Raloxifene on Risk of Breast Cancer in Postmenopausal Women

Cummings, Steven R.; Eckert, Stephen; Krueger, Kathryn A.; Grady, Deborah; Powles, Trevor J.; Cauley, Jane A.; Norton, Larry; Nickelsen, Thomas; Bjarnason, Nina H.; Morrow, Monica; Lippman, Marc E.; Black, Dennis M.; Glusman, J. E.; Costa, Alberto; Jordan, V. Craig

doi:10.1001/jama.281.23.2189

Cited by 1,657 publications

(301 citation statements)

References 41 publications

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“…20 Two recent randomized trials have shown a reduction in the incidence of primary breast cancer in postmenopausal women receiving long term anti-estrogen therapy. 21,22 In both trials, the risk reduction was almost completely con®ned to ER positive tumors.…”

Section: Progression Of Intraductal Carcinomamentioning

confidence: 98%

Adiposity as a risk determinant for postmenopausal breast cancer

2000

Int J Obes

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BACKGROUND: Cross-cultural studies have long suggested that the high incidence of breast cancer in developed Western countries may be linked to the high prevalence of obesity and to high total energy intake. Recent studies show that hyperinsulinemia, increased concentration of insulin-like growth factor 1 and greater abdominal fat accumulation are markers of high risk for breast cancer. Increased serum concentrations of free estradiol and free testosterone are similar risk markers and are frequent concomitants of hyperinsulinemia. MECHANISMS: The mechanism by which such metabolic ± endocrine abnormality may promote mammary carcinogenesis is uncertain, but its effect is likely to predominate in the years approaching the menopause when obesity is common among Western women. In obese subjects, enlargement of adipose deposits is known to produce an excess of free fatty acids and tumor necrosis factor alpha, both of which may be involved in the pathogenesis of insulin resistance. In middle-aged women, the concomitants of hyperinsulinemia may activate invasive and proliferative activity in preneoplastic mammary lesions such as in situ duct carcinoma of the comedo type. This will enhance the risk of progression to invasive breast cancer, which is likely to manifest clinically mainly after the menopause. CONCLUSION: Weight reduction combined with a program of regular physical exercise has been shown to reduce both estrogen and insulin concentrations in obese women and such a regimen might be tested in clinical trials for an effect on breast cancer risk in obese women. Intervention is best begun around the age of 45 y, this being the age when in situ duct carcinoma would normally begin to show evidence of spontaneous involution in women without clinical evidence of invasive breast cancer.

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Section: Progression Of Intraductal Carcinomamentioning

confidence: 98%

Adiposity as a risk determinant for postmenopausal breast cancer

2000

Int J Obes

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“…Subgroup analysis of the data from the Multiple Outcomes of Raloxifene (MORE) trial revealed that administration of raloxifene was associated with a 75% reduction in the incidence of invasive breast cancer without a concurrent increase in the incidence of endometrial cancers (Cummings et al, 1999). This finding has led to the ongoing randomized study of TAM and raloxifene (STAR) in breast cancer prevention.…”

Section: Antiestrogensmentioning

confidence: 99%

Antiestrogen resistance in breast cancer and the role of estrogen receptor signaling

et al. 2003

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“…However, the recognition that raloxifene maintains bone density (4,5) and inhibits mammary carcinogenesis in the rat (6,7) illustrates the concept of selective estrogen receptor modulation. Raloxifene is used for the prevention of osteoporosis in postmenopausal women (8), and treatment is associated with a reduced incidence of breast cancer (9).…”

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confidence: 99%

Structure-Function Relationships of the Raloxifene-Estrogen Receptor-α Complex for Regulating Transforming Growth Factor-α Expression in Breast Cancer Cells

Liu¹,

Park²,

Bentrem³

et al. 2002

Journal of Biological Chemistry

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Amino acid Asp-351 in the ligand binding domain of estrogen receptor ␣ (ER␣) plays an important role in regulating the estrogen-like activity of selective estrogen receptor modulator-ER␣ complexes. 4-Hydroxytamoxifen is a full agonist at a transforming growth factor ␣ target gene in situ in MDA-MB-231 human breast cancer cells stably transfected with the wild-type ER␣. In contrast, raloxifene (Ral), which is also a selective estrogen receptor modulator, is a complete antiestrogen in this system. Because D351G ER␣ allosterically silences activation function-1 activity in the 4-hydroxytamoxifen-ER␣ complex with the complete loss of estrogenlike activity, we examined the converse interaction of amino acid 351 and the piperidine ring of the antiestrogen side chain of raloxifene to enhance estrogen-like action. MDA-MB-231 cells were either transiently or stably transfected with Asp-351 (the wild type), D351E, D351Y, or D351F ER␣ expression vectors. Profound differences in the agonist and antagonist actions of Ral⅐ER␣ complexes were noted only in stable transfectants. The agonist activity of the Ral⅐ER␣ complex was enhanced with D351E and D351Y ER␣, but raloxifene lost its agonist activity with D351F ER␣. The distance between the piperidine nitrogen of raloxifene and the negative charge of amino acid 351 was critical for estrogen-like actions. The role of the piperidine ring in neutralizing Asp-351 was addressed using compound R1h, a raloxifene derivative replacing the nitrogen on its piperidine ring with a carbon to form cyclohexane. The derivative was a potent agonist with wild type ER␣. These results support the concept that the side chain of raloxifene shields and neutralizes the Asp-351 to produce an antiestrogenic ER␣ complex. Alteration of either the side chain or its relationship with the negative charge at amino acid 351 controls the estrogen-like action at activating function 2b of the selective estrogen receptor modulator ER␣ complex.Raloxifene (Ral) 1 (see Fig. 1) is a polyhydroxyphenyl benzothiophene antiestrogen that has low estrogen agonist activity in the rodent uterus (1). The compound originally referred to as Ly156758 or keoxifene was abandoned for development as a treatment for breast cancer (2), because its bioavailability was less than 2% administered dose (3). However, the recognition that raloxifene maintains bone density (4, 5) and inhibits mammary carcinogenesis in the rat (6, 7) illustrates the concept of selective estrogen receptor modulation. Raloxifene is used for the prevention of osteoporosis in postmenopausal women (8), and treatment is associated with a reduced incidence of breast cancer (9).Tamoxifen is the prototype selective estrogen receptor modulator (SERM) that is used clinically for the treatment and prevention of breast cancer (10, 11) with the ability to maintain bone density in postmenopausal women (12). However, tamoxifen therapy is also associated with estrogen-like effects in the uterus with an increased incidence of endometrial cancer (13). Raloxifene is currently being ...

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The Effect of Raloxifene on Risk of Breast Cancer in Postmenopausal Women

Cited by 1,657 publications

References 41 publications

Adiposity as a risk determinant for postmenopausal breast cancer

Adiposity as a risk determinant for postmenopausal breast cancer

Antiestrogen resistance in breast cancer and the role of estrogen receptor signaling

Structure-Function Relationships of the Raloxifene-Estrogen Receptor-α Complex for Regulating Transforming Growth Factor-α Expression in Breast Cancer Cells

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