Estrogen Receptors as Therapeutic Targets in Breast Cancer

Ariazi, Eric A.; Ariazi, Jennifer L.; Cordera, Fernando; Jordan, V. Craig

doi:10.1002/9783527623297.ch5

Cited by 83 publications

(25 citation statements)

References 358 publications

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“…ERb-mediated apoptosis is associated with increased Aif activation, while ERa-mediated apoptosis is associated with activation of caspase 9. These parenchymal changes impact the stromal-parenchymal interactions, and there is an increase in stromal laminin redistribution with a concomitant increase in epithelial integrin a6, which contributes to enhance the apoptotic events that estrogens might be exploited therapeutically in tumors which are resistant to other endocrine treatments [16,62], and PPT seems to be a better therapeutic option than DPN. A question that still lingers, and is actively being studied in our lab, is the identification of the tumors that will be stimulated by estrogens or ER agonists and those that will be inhibited.…”

Section: Discussionmentioning

confidence: 97%

Inhibition of mammary tumor growth by estrogens: is there a specific role for estrogen receptors alpha and beta?

Soldati

Wargon

Cerliani

et al. 2009

Breast Cancer Res Treat

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To evaluate the extent to which each estrogen receptor (ER) subtype contributes to the stimulation or to the inhibition of mammary tumor growth, we evaluated the effects of specific agonists in MC4-L2 cells, which are stimulated by 17β-estradiol (E(2)), and in mammary carcinomas of the MPA mouse breast cancer model, which are inhibited by E(2). Both express ERα and ERβ. In MC4-L2 cells, 4,4',4"-(4-propyl-(1H)-pyrazole-1,3,5-triyl)trisphenol (PPT; ERα agonist) and (4-hydroxy-phenyl)-propionitrile (DPN; ERβ agonist) stimulated cell proliferation, whereas the opposite occurred in C4-HI primary cultures. The inhibitory effect was associated with a decrease in ERα and cyclin D1 expression and an increase in progesterone receptor (PR) expression as well as in the Bax/Bcl-xl ratio. In vivo, mice carrying C4-HI or 32-2-HI tumors were treated with E(2), PPT or DPN (3 mg/kg/day) or with vehicle. PPT and DPN inhibited tumor size, as did E(2), during the first 72 h. After a few days, DPN-treated tumors started to grow again, while PPT-treated tumors remained quiescent for a longer period of time. A pronounced decrease in the mitotic index and an increase in the apoptotic index was associated with tumor regression. All treated tumors showed: (a) an increase in integrin α6 and Bax expression, (b) an increased stromal laminin redistribution, and (c) a decrease in ERα, Bcl-xl and Bcl-2 expression (P < 0.001). Apoptosis-inducing factor (Aif) expression was increased in DPN-treated tumors, while active caspase 9 was up-regulated in PPT-treated mice, demonstrating the involvement of the intrinsic apoptotic pathway in estrogen-induced regression in this model. In conclusion, our data indicate that although there may be some preferences for activation pathways by the different agonists, the stimulatory or inhibitory effects triggered by estrogens are cell-context dependent rather than ER isoform dependent.

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Section: Discussionmentioning

confidence: 97%

Inhibition of mammary tumor growth by estrogens: is there a specific role for estrogen receptors alpha and beta?

Soldati

Wargon

Cerliani

et al. 2009

Breast Cancer Res Treat

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“…Given the established role of ERa on the etiology and pathophysiology of breast cancer, the second leading cause of cancer death in women, selective ER modulation is an important strategy in the treatment of this disease [14][15][16]. The ER modulators tamoxifen (generic) and fulvestrant (Faslodex 1 ) are well-known drugs employed in cancer therapy.…”

Section: Introductionmentioning

confidence: 99%

Structural and chemical basis for enhanced affinity and potency for a large series of estrogen receptor ligands: 2D and 3D QSAR studies

Salum

Polikarpov

Andricopulo

2007

Journal of Molecular Graphics and Modelling

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“…Even though women treated with idoxifene had decreased bone resorption [43], in early phase II studies, increased endometrial thickness and increased polyps and pelvic prolapsed emerged [44][45][46]. Thus development of this drug was curtailed.…”

Section: Serms That Are No Longer Being Developedmentioning

confidence: 99%

SERMs and SERMs with estrogen for postmenopausal osteoporosis

Bolognese

2010

Rev Endocr Metab Disord

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Bone loss with aging places postmenopausal women at a higher risk for osteoporosis and its consequences such as fractures, pain, disability, and increased morbidity and mortality. Approximately 200 million patients worldwide are affected. The Third National Health and Nutrition Examination Survey (NHANES III) estimated that up to 18% of US women aged 50 and older have osteoporosis and up to 50% have osteopenia. Greater than 2 million osteoporotic related fractures occurred in the United States with direct healthcare costs exceeding $17 billion. Hormone Replacement Therapy (HRT) was a popular option for postmenopausal women before the Women's Health Initiative (WHI). Several agents are available in the U.S., including bisphosphonates, hormone therapy, calcitonin, parathyroid hormone and the selective estrogen receptor modulator (SERM) raloxifene. There are concerns about long term safety and compliance. Therefore, other agents are under investigation. SERMs are a diverse group of agents that bind to the estrogen receptor and each SERM appears to have a unique set of clinical responses, which are not always consistent with the typical responses seen with other SERMs. This article will discuss the SERMs approved in the United States, tamoxifene and raloxifene, and investigational SERMs. The ideal SERM would include the beneficial effects of estrogen in bone, heart and the central nervous system, with neutral or antagonistic effects in tissues where estrogen effects are undesirable(breast and endometrium). A new target in treating postmenopausal osteoporosis is the tissue estrogen complex or the pairing of a SERM with a conjugated estrogen known as a tissue selective estrogen complex (TSEC). This novel approach is currently being evaluated with bazodoxifene which could yield the beneficial effects of estrogens and SERMS, while potentially being more tolerable and safer than either therapy alone.

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Estrogen Receptors as Therapeutic Targets in Breast Cancer

Cited by 83 publications

References 358 publications

Inhibition of mammary tumor growth by estrogens: is there a specific role for estrogen receptors alpha and beta?

Inhibition of mammary tumor growth by estrogens: is there a specific role for estrogen receptors alpha and beta?

Structural and chemical basis for enhanced affinity and potency for a large series of estrogen receptor ligands: 2D and 3D QSAR studies

SERMs and SERMs with estrogen for postmenopausal osteoporosis

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