Avoiding the Bad and Enhancing the Good of Soy Supplements in Breast Cancer

Jordan, V. Craig

doi:10.1093/jnci/dju233

Cited by 21 publications

(22 citation statements)

References 19 publications

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“…Timing relative to menopause is important ie: more breast cancer risk occurs the nearer to menopause. This concept (140) is summarized in Figure 6 which now establishes rules for the actions of different estrogens; estrogen deprivation for 5 years creates populations of breast cancer cells vulnerable to estrogen induced apoptosis.…”

Section: Hormone Replacement Therapy In Postmenopausal Womenmentioning

confidence: 99%

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The new biology of estrogen-induced apoptosis applied to treat and prevent breast cancer

Jordan¹

2014

Endocrine-Related Cancer

121

100

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The successful use of high dose synthetic estrogens to treat post-menopausal metastatic breast cancer, is the first effective “chemical therapy” proven in clinical trial to treat any cancer. This review documents the clinical use of estrogen for breast cancer treatment or estrogen replacement therapy (ERT) for postmenopausal hysterectomized women which can either result in breast cancer cell growth or breast cancer regression. This has remained a paradox since the 1950s until the discovery of the new biology of estrogen induced apoptosis at the end of the 20th century. The key to triggering apoptosis with estrogen is the selection of breast cancer cell populations that are resistant to long term estrogen deprivation. However, through trial and error estrogen independent growth occurs. At the cellular level, estrogen induced apoptosis is dependent upon the presence of the estrogen receptor (ER) which can be blocked by non-steroidal or steroidal anti-estrogens. The shape of an estrogenic ligand programs the conformation of the ER complex which in turn can modulate estrogen induced apoptosis: class I planar estrogens (eg: estradiol) trigger apoptosis after 24 hours whereas class II angular estrogens (eg: bisphenol triphenylethylene) delay the process until after 72 hours. This contrasts with paclitaxel that causes G2 blockade with immediate apoptosis. The process is complete within 24 hours. Estrogen induced apoptosis is modulated by glucocorticoids and cSrc inhibitors but the target mechanism for estrogen action is genomic and not through a non-genomic pathway. The process is step wise through the creation of endoplasmic reticulum stress and, inflammatory responses that then initiate an unfolded protein response. This in turn initiates apoptosis through the intrinsic pathway (mitochondrial) with subsequent recruitment of the extrinsic pathway (death receptor) to complete the process. The symmetry of the clinical and laboratory studies now permits the creation of rules for the future clinical application of ERT or phytoestrogen supplements: a five year gap is necessary after menopause to permit the selection of estrogen deprived breast cancer cell populations to become vulnerable to apoptotic cell death. Earlier treatment with estrogen around the menopause encourages ER positive tumor cell growth, as the cells are still dependent on estrogen to maintain replication within the expanding population. An awareness of the evidence that the molecular events associated with estrogen induced apoptosis can be orchestrated in the laboratory in estrogen deprived breast cancers, now support the clinical findings for the treatment of metastatic breast cancer following estrogen deprivation, decreases in mortality following long term antihormonal adjuvant therapy, and the results of ERT and ERT plus progestin in the Women’s Health Initiative for women over the age of 60. Principles have emerged to understand and apply physiologic estrogen therapy appropriately by targeting the correct patient populations.

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Section: Hormone Replacement Therapy In Postmenopausal Womenmentioning

confidence: 99%

“…Laboratory studies illustrate that the constituents of conjugated equine estrogen (CEE)(196), the endocrine disruptor bisphenol A (163) and phytoestrogens (143) can trigger cell replication or apoptosis dependent upon the cell populations and its natural estrogen rich or austere environment. Reproduced with permission from (140). …”

Section: Figurementioning

confidence: 99%

The new biology of estrogen-induced apoptosis applied to treat and prevent breast cancer

Jordan¹

2014

Endocrine-Related Cancer

121

100

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“…It is important to consider timing when considering the implications of this work; timing of HRT can make a dramatic difference in response to treatment (31, 32). MCF-7:5C cells represent long-term estrogen-deprived cells, we sought this is the biological context required in the patient as well to replicate the patient population in the WHI CEE alone trial (15).…”

Section: Discussionmentioning

confidence: 99%

Molecular Modulation of Estrogen-Induced Apoptosis by Synthetic Progestins in Hormone Replacement Therapy: An Insight into the Women's Health Initiative Study

2014

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Hormone replacement therapy (HRT) is widely used to manage menopausal symptoms in women, and can comprise an estrogen alone or an estrogen combined with a progestin. The Women’s Health Initiative demonstrated in their randomized trials that estrogen alone HRT decreases the risk of breast cancer in post-menopausal women, while combined estrogen plus a progestin (medroxyprogesterone acetate, MPA) HRT increases this risk. Long-term estrogen-deprived MCF-7:5C cells were used to model the post-menopausal breast cancer cell environment. MPA is able to modify E2-induced apoptosis in MCF-7:5C cells. MPA, similar to dexamethasone (Dex) increases GR transcriptional activity, increases SGK1, a GR target gene, and can be blocked by RU486 (an antiglucocorticoid), suggesting it functions through the GR. Norethindrone acetate (NETA), another progestin used in HRT, acts like an estrogen at high doses, up-regulating ER-target genes and generating apoptosis in MCF-7:5C cells. The data suggests that women taking HRT comprising an estrogen plus MPA may have an increased the risk of breast cancer due to MPA acting as a glucocorticoid and blunting E2-induced apoptosis in this environment. Therefore, perhaps other approved progestins (e.g. NETA) should be considered as alternatives to MPA.

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“…In summary, the data from recent in vitro and in vivo studies converge in one key concept: estrogen and phytoestrogen are ''bad" when supplemented in ''5 year gap" menopausal women but, if the plasmatic concentrations of these compounds reach hundred nanomolar a decade following menopause onset (>5 years), then their chemopreventive effect could switch to ''good" (Jordan, 2014).…”

Section: Genistein As a Modulator Of Er In Bc: In Vitro And In Vivo Smentioning

confidence: 99%

“…In other words, BC cells from young or early post-menopausal (<5 years) women, use isoflavone as a ''substitute fuel" to grow and survive in estrogen-austere conditions (Jordan, 2014). In a different cellular background, when BC cells grow independently of estrogens, as in older post-menopausal woman (>5 years), high levels of phyto-estrogens could induce massive apoptotic cell death (Obiorah, Fan, & Jordan, 2014).…”

Section: Genistein As a Modulator Of Er In Bc: In Vitro And In Vivo Smentioning

confidence: 99%

Understanding genistein in cancer: The “good” and the “bad” effects: A review

et al. 2016

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Avoiding the Bad and Enhancing the Good of Soy Supplements in Breast Cancer

Cited by 21 publications

References 19 publications

The new biology of estrogen-induced apoptosis applied to treat and prevent breast cancer

The new biology of estrogen-induced apoptosis applied to treat and prevent breast cancer

Molecular Modulation of Estrogen-Induced Apoptosis by Synthetic Progestins in Hormone Replacement Therapy: An Insight into the Women's Health Initiative Study

Understanding genistein in cancer: The “good” and the “bad” effects: A review

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