Physiologic Effects of Steroid Hormones and Postmenopausal Hormone Replacement on the Female Breast and Breast Cancer Risk

Mustafa, Isha A.; Bland, Kirby I.

doi:10.1097/00000658-199811000-00003

Cited by 14 publications

(9 citation statements)

References 99 publications

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“…Experimental evidence supports a role for estrogens in DNA synthesis and in general cellular growth-stimulatory pathways [Darbre et al, 1983;Lykkesfeldt and Briand, 1986;Mustafa and Bland, 1998;Castoria et al, 1999]. However, a full understanding of what distinctions define normal hormonally induced growth and differentiation and hormonally induced transformation will require a better understanding of interpathway regulation following hormonal stimulation.…”

Section: Discussionmentioning

confidence: 99%

Increased proteasome‐dependent degradation of estrogen receptor‐alpha by TGF‐β1 in breast cancer cell lines

Petrel

Brueggemeier

2002

J of Cellular Biochemistry

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Normal mammary epithelial cells are rapidly induced to G 1 arrest by the widely expressed cytokine, transforming growth factor beta (TGF-β1). Studies in established breast cancer cell lines that express the estrogen receptor alpha (ERα) have demonstrated loss of this responsiveness. This inverse correlation suggests interpathway signaling important to cell growth and regulation. The adenocarcinoma breast cell line BT474, which was not growth arrested by TGF-β1, was used as a model of estrogen-inducible growth to explore interpathway crosstalk. Although BT474 cells were not growth-arrested by TGF-β1 as determined by flow cytometry analysis and 5′-bromo-3′-deoxyuridine incorporation into DNA, estrogen receptor protein levels were attenuated by 100 pM TGF-β1 after 6 h. This decrease in ERα reached 50% of untreated control levels by 24 h of treatment and was further supported by a 50% decrease in estrogen-inducible DNA synthesis. Inspection of ERα transcripts suggested that this decrease was primarily the result of altered ERα protein stability or availability. Use of the proteasome inhibitor, MG132, abolished all effects on ERα by TGF-β1. Collectively, this data supports a role for TGF-β1 in regulating the growth of otherwise insensitive breast cancer cells through modulation of ERα stability.Keywords breast cancer; estrogen receptor alpha; transforming growth factor beta; ubiquitin; proteasome; cell proliferation Breast cancer is a leading cause of death among women worldwide and an estimated 203,500 new cases will be diagnosed in the US alone in 2002 [American Cancer Society, 2001]. Systemic and locally produced estrogens are intimately associated with increased risk for breast cancer development. Early menarche and late menopause increase the lifetime exposure to estrogens and as much as a 20% decrease in breast cancer risk is observed for each year this exposure is shortened [Kelsey, 1979]. By the same token, increased and sustained physical activity can reduce the total lifetime ovulatory period and has been shown to confer a significant decrease in breast cancer risk [Bernstein et al., 1994]. Numerous epidemiological studies of breast cancer risk in postmenopausal women have shown higher mean serum estrogen concentrations than disease-free control subjects [Thomas et al., 1997]. These and additional risk factors share a common theme, i.e., increased lifetime tissue exposure to estrogens. Thus, estrogen exposure is a central and reoccurring phenomenon in breast cancer etiology.Although many risk factors have been identified, the molecular mechanisms underlying the initiation and progression of breast cancer are still elusive. Estrogens such as 17β-estradiol (E 2 ) play a key role in the development and maintenance of the mature mammary gland. The most well characterized cellular receptor for this steroid hormone is the estrogen receptor alpha (ERα) [Moggs and Orphanides, 2001]. This receptor is expressed in a tissue specific manner and regulates growth and differentiation in response to hormonal stimul...

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Section: Discussionmentioning

confidence: 99%

Increased proteasome‐dependent degradation of estrogen receptor‐alpha by TGF‐β1 in breast cancer cell lines

Petrel

Brueggemeier

2002

J of Cellular Biochemistry

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“…Because only about half of breast cancer risk can be attributed to established risk factors, including sex, advancing age, early menarche, late menopause, late age at first birth, and first-degree relative with breast cancer (2,3), there has been continued interest in the role environmental contaminants may play in unexplained breast cancer risk (4,5). Ovarian hormones, including estrogen and progesterone, may affect breast cancer risk by affecting rates of cell proliferation in the breast or by supporting the growth of estrogendependent breast tumors (6)(7)(8)(9)(10). Hormonally active agents found in the environment that affect breast cell proliferation by acting as estrogen mimics or by disrupting pathways leading to enhanced breast cell proliferation may also affect breast cancer risk.…”

mentioning

confidence: 99%

Pesticides and breast cancer risk: a review of DDT, DDE, and dieldrin.

Snedeker

2001

Environ Health Perspect

240

140

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Established risk factors for breast cancer explain breast cancer risk only partially. Hence, there has been interest in evaluating what role environmental chemicals, especially those with evidence of being hormonally active agents, play in breast cancer risk. Organochlorine pesticides have received the most attention because of their persistence in the environment, ability to concentrate up the food chain, continued detection in the food supply and breast milk, and ability to be stored in the adipose tissue of animals and humans. Although several early descriptive studies and a cohort study identified a strong positive association with breast cancer risk and adipose or blood levels of the organochlorine pesticide dichlorodiphenyltrichloroethane (DDT) and/or its metabolite dichlorodiphenyldichloroethylene (DDE), most of the more recent case--control and nested case--control studies have not supported this association. In this review I discuss these findings and explore how exposure to different forms of DDT with varying estrogenicities may have affected the results of these studies. I also address how other factors influence the interpretation of the studies on DDT, DDE, and breast cancer risk. These include the effect of analytic methods, dietary factors, menopausal status, use of different types of control populations, lactation history, estrogen receptor status, ethnic/racial subgroups, breast tumor characteristics, and polymorphisms. I also discuss the emerging research on whether serum levels of the persistent organochlorine insecticide dieldrin are related to breast cancer risk in Danish and American women. Further research needs are also identified.

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“…Isso leva a inferir que o progestogênio potencializaria o efeito estrogênico e que não haveria necessidade da ação estrogênica prévia para sua ação. Estudos prévios observaram que a administração de progestogênio induz maior proliferação de células acinares e atividade mitótica, à semelhança da ação estrogênica, propondo que o estrogênio atuaria estimulando a proliferação celular e o progestagênio faria o mesmo, além de induzir a diferenciação quando há ação estrogênica 39,40,41,42 . Os esteróides sexuais, mesmo que acarretem a diferenciação celular ao estimularem a atividade proliferativa mamária, podem propiciar alterações carcinogenéticas, celulares.…”

Section: Sex Steroidsunclassified

Histologia mamária após uso de esteróides sexuais - estudo em ratas

Vicelli¹,

Gurgel²,

Alvarenga³

2006

Rev. Assoc. Med. Bras.

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RESUMOOBJETIVO. Avaliar as alterações histológicas em mamas de ratas submetidas à terapêutica com estrogênio, progestogênio e tibolona. MÉTODOS. Estudo experimental com 40 ratas, sendo 20 sem prole (grupo A) e 20 com prole (grupo B). Todas as ratas foram castradas e, após quatro semanas, alocadas aleatoriamente em subgrupos: A1, A2, A3, A4, A5 e B1, B2, B3, B4, B5. Os esteróides foram administrados da seguinte forma: A1 e B1 -benzoato de estradiol; A2 e B2 -acetato de medroxiprogesterona; A3 e B3 -benzoato de estradiol e acetato de medroxiprogesterona; A4 e B4 -tibolona; A5 e B5 -placebo. Após dez semanas de tratamento, os animais foram sacrificados e suas glândulas mamárias submetidas à análise histológica. Os parâmetros avaliados foram: proliferação epitelial, atividade secretora e atipias epiteliais nas unidades de ductos ou alvéolos terminais. A associação entre os achados histológicos e os esquemas terapêuticos foi avaliada por meio do odds ratio e intervalo de confiança de 95%. RESULTADOS. Alterações histológicas foram observadas em 29 ratas: hiperplasia moderada (52,5%), hiperplasia alvéolo-nodular (42,5%), atipia sem proliferação (35%), hiperplasia leve (32,5%), atividade secretora (20%) e hiperplasia severa (5%). Em ratas sem prole observou-se 1,3 mais chance, em relação ao grupo controle, de apresentar hiperplasia alvéolo-nodular no grupo que recebeu estrogênio, hiperplasia moderada no grupo tratado com progestogênio, e hiperplasia alvéolo-nodular e atipia sem proliferação epitelial com a associação entre estrogênio e progestogênio. CONCLUSÃO. Hiperplasia moderada e atipia epitelial associaram-se à terapia combinada de estrogênio e progestogênio, e o antecedente de prole reduziu a ocorrência destas alterações e de hiperplasia alvéolo-nodular. INTRODUÇÃONas últimas décadas, estudos demonstraram os benefícios da terapia hormonal (TH) no climatério, representados pelo alívio de sintomas, prevenção e tratamento da atrofia urogenital e da osteoporose 1,2,3 . A despeito dos benefícios da TH, o seu uso pode apresentar alguns efeitos indesejáveis, como o aumento do risco de câncer de mama 4,5,6 . Existem diversos esquemas de TH, porém os mais utilizados são o uso exclusivo de estrogênio ou a associação deste com progestogênio.Além destes esteróides, a tibolona -um esteróide sintético -vem sendo utilizada para o tratamento dos sintomas climatéricos, possuindo ações estrogênica, progestogênica e androgênica 7 . Estudos experimentais demonstraram que, in vitro, a tibolona reduz a proliferação de células mamárias e a produção de estradiol 8 , enquanto in vivo reduz o volume tumoral de carcinomas mamários 9 . Contudo, estudos de coorte demonstraram aumento do risco relativo para desenvolvimento de câncer de mama em usuárias de tibolona 6,10 . Dessa forma, permanece incerto o papel da tibolona na indução de alterações proliferativas e no risco de câncer de mama. Hofseth et al. (1999) 11 , estudando biópsias de mamas de mulheres na pós-menopausa, observaram que a proliferação do epitélio mamário foi maior em usuária...

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Physiologic Effects of Steroid Hormones and Postmenopausal Hormone Replacement on the Female Breast and Breast Cancer Risk

Cited by 14 publications

References 99 publications

Increased proteasome‐dependent degradation of estrogen receptor‐alpha by TGF‐β1 in breast cancer cell lines

Increased proteasome‐dependent degradation of estrogen receptor‐alpha by TGF‐β1 in breast cancer cell lines

Pesticides and breast cancer risk: a review of DDT, DDE, and dieldrin.

Histologia mamária após uso de esteróides sexuais - estudo em ratas

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