Estrogen Plus Progestin and Colorectal Cancer Incidence and Mortality

Simon, Michael S.; Chlebowski, Rowan T.; Wactawski‐Wende, Jean; Johnson, Karen C.; Muskovitz, Andrew A.; Kato, Ikuko; Young, Alicia; Hubbell, F. Allan; Prentice, Ross L.

doi:10.1200/jco.2012.42.7732

Cited by 97 publications

(78 citation statements)

References 39 publications

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“…When apoptosis was measured in the tumors of the ERbKO mice, it was found that E 2 treatment resulted in no significant change compared with the cholesterol-treated ERbKO mice. Similarly, data from human trials determining the effects of combined estrogen and progestin therapy in postmenopausal women showed that the combined HRT reduced the incidence of colon tumors in these women; however, the tumors that were detected were at a more advanced stage (Simon et al 2012). The fact that a similar phenomenon was observed in human tissues supports the results obtained from mice in this study.…”

Section: Discussionsupporting

confidence: 80%

A novel shift in estrogen receptor expression occurs as estradiol suppresses inflammation-associated colon tumor formation

Armstrong¹,

Billimek²,

Allred³

et al. 2013

Endocrine-Related Cancer

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Postmenopausal women on estrogen replacement therapy (ERT) have a reduced risk of developing colon cancer compared with postmenopausal women not on ERT, suggesting a role for estradiol (E 2 ) in protection against this disease. To determine whether E 2 protects against inflammation-associated colon cancer when administered following the initiation of colonic DNA damage, in this study, we implanted E 2 -containing pellets into mice after co-treatment with azoxymethane and two rounds of dextran sulfate sodium (DSS). Wild-type (WT) E 2 -treated mice had reduced numbers and average area of adenocarcinomas compared with the control mice. These effects were lost in estrogen receptor-b (Erb (Esr2)) knockout mice. Surprisingly, apoptosis was reduced and cell proliferation was increased in sections from tumors of the WT E 2 mice compared with the WT control mice. These findings are probably due, in part, to a reduction in ERb expression in colonic epithelial cells as the cells progressed from a non-malignant to a cancerous state as enhanced apoptosis was observed in normal colonocytes expressing higher levels of ERb. Furthermore, epithelial cells within the tumors had dramatically increased ERa mRNA and protein expression compared with the non-diseased mice. We conclude that while E 2 treatment resulted in an overall suppression of colonic adenocarcinoma formation, reduced ERb expression accompanied by enhanced ERa expression caused an altered colonocyte response to E 2 treatment compared with the earlier stages of colon cancer development. These data are the first examples of decreased ERb expression concurrent with increased ERa expression as a disease develops and highlight the importance of understanding the timing of E 2 exposure with regard to the prevention of inflammation-associated colon cancer.

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Section: Discussionsupporting

confidence: 80%

A novel shift in estrogen receptor expression occurs as estradiol suppresses inflammation-associated colon tumor formation

Armstrong¹,

Billimek²,

Allred³

et al. 2013

Endocrine-Related Cancer

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show abstract

“…2). It is important to note, however, that the progesterone receptor, under intense investigation in breast cancer 21 , may also be involved in cancer of non-reproductive organs, like what recently reported for lung NSCLC 22 and colon cancer 23 . a) Stem cell renewal : Specific ablation of estrogen receptor α, β and androgen receptor affects homeostasis and/or regeneration of organs unrelated to reproductive functions, such as lung 24, , colon 25 and skin [26][27][28] .…”

Section: Introduction (Epidemiology)mentioning

confidence: 78%

Sexual dimorphism in cancer

et al. 2016

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The incidence of many cancer types is significantly higher in the male than female populations, with associated differences in survival. Occupational and/or behavioral factors are well known underlying determinants. However, cellular/molecular differences between the two sexes are also likely to be important. We are focusing here on the complex interplay that sexual hormones and sex chromosomes can have in intrinsic control of cancer initiating cell populations, tumor microenvironment and systemic determinants of cancer development like the immune system and metabolism. A better appreciation of these differences between the two sexes could be of substantial value for cancer prevention as well as treatment.3 Introduction (Epidemiology)

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“…Observational studies have consistently found an association with hormone therapy use and lower colorectal cancer incidence (66, 67). With respect to colorectal cancer, in the estrogen plus progestin randomized WHI trial, there were 44% fewer colorectal cancers in the combined hormone therapy group diagnosedduring a mean of 5.6 years intervention (nominal p = 0.003) (68).…”

Section: Other Cancersmentioning

confidence: 99%

“…However, the cancers had more lymph node involvement (59% vs 29%, p = 0.003) and were diagnosed at substantially higher stage (regional/metastatic, 76% vs 49%, respectively, p = 0.004). Now with longer 11.6 years follow-up, there is a non-significant increase indeaths from colorectal cancer in the combined hormone therapy group (37 vs 27 deaths; 0.04% vs 0.03%: HR 1.29 95% CI 0.78-2.11, p = 0.320) (67). These data are not compatible with a clinically meaningful reduction in colorectal cancer since this disease carries a 30% 5 year mortality risk (69).…”

Section: Other Cancersmentioning

confidence: 99%

Menopausal hormone therapy and cancer: Changing clinical observations of target site specificity

Chlebowski

Anderson

2014

Steroids

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Menopausal hormone therapy with estrogen plus progestin or estrogen alone (for women with prior hysterectomy) is still used by millions of women for climacteric symptom management throughout the world. Until 2002, hormone therapy influence on cancer risk and other chronic diseases was determined through observational study reports. Since then, results from the Women's Health Initiative randomized, placebo-controlled hormone therapy trials have substantially changed concepts regarding estrogen plus progestin and estrogen alone influence on the most common cancers in postmenopausal women. In these trials, estrogen plus progestin significantly increased breast cancer incidence and deaths from breast cancer, significantly increased deaths from lung cancer, significantly decreased endometrial cancer, and did not have a clinically significant influence on colorectal cancer. In contrast, estrogen alone use in women with prior hysterectomy significantly reduced breast cancer incidence and deaths from breast cancer without significant influence on colorectal cancer or lung cancer. These complex results are discussed in the context of known potential mediating mechanisms of action involved in interactionwith steroid hormone receptors.

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Estrogen Plus Progestin and Colorectal Cancer Incidence and Mortality

Cited by 97 publications

References 39 publications

A novel shift in estrogen receptor expression occurs as estradiol suppresses inflammation-associated colon tumor formation

A novel shift in estrogen receptor expression occurs as estradiol suppresses inflammation-associated colon tumor formation

Sexual dimorphism in cancer

Menopausal hormone therapy and cancer: Changing clinical observations of target site specificity

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