Breast Cancer Abstracts 5


ACOG Committee Opinion No. 659: The Use of Vaginal Estrogen in Women With a History of Estrogen-Dependent Breast Cancer.
            (American and Farrell, 2016) Download
Cancer treatment should address female-specific survivorship issues, including the hypoestrogenic- related adverse effects of cancer therapies or of natural menopause in survivors. Systemic and vaginal estrogen are widely used for symptomatic relief of vasomotor symptoms, sexual dysfunction, and lower urinary tract infections in the general population. However, given that some types of cancer are hormone sensitive, there are safety concerns about the use of local hormone therapy in women who currently have breast cancer or have a history of breast cancer. Nonhormonal approaches are the first-line choices for managing urogenital symptoms or atrophy-related urinary symptoms experienced by women during or after treatment for breast cancer. Among women with a history of estrogen-dependent breast cancer who are experiencing urogenital symptoms, vaginal estrogen should be reserved for those patients who are unresponsive to nonhormonal remedies. The decision to use vaginal estrogen may be made in coordination with a woman's oncologist. Additionally, it should be preceded by an informed decision-making and consent process in which the woman has the information and resources to consider the benefits and potential risks of low-dose vaginal estrogen. Data do not show an increased risk of cancer recurrence among women currently undergoing treatment for breast cancer or those with a personal history of breast cancer who use vaginal estrogen to relieve urogenital symptoms.

High serum estradiol confers no risk for breast cancer: another disparity for sub Saharan Africa women
            (Awio et al., 2012) Download
INTRODUCTION: There are breast cancer epidemiological and tumor behaviour disparities between black women in sub Saharan Africa and their counter parts in western high resource countries. In Uganda, the incidence of breast cancer has nearly tripled in over a four decades for uncertain reasons. High serum estradiol is a known risk factor for breast cancer among women in high resourced nations. The objective of this study was to establish whether high serum estradiol is an associated risk for breast cancer amongst a group of black Ugandan women. METHODS: A case control study, conducted over eight month period with incident breast cancer as cases and the controls were without breast cancer but at risk and representative of the population from which the cases were chosen. Questionnaires were administered, clinical examination was done, serum estradiol level estimation was done using cobase immunoassay analyzer using Electro chemiluminescence Immuno assay (ECLIA). Data was analyzed using logistic regression model, and a p - value of less than 0.05 was considered significant. IRB approval was secured. RESULTS: A total of 140 women participated, 70 cases and 70 controls. The median estrogen levels was 43.2 pg/ml with IQR of 18.48 to 75.8 pg/ml, the value was higher among premenopausal women than those without cancer but with no statistical significance. No association was found between level of estradiol and breast cancer (p 0.647). The median oestrogen levels were significantly higher than normal levels in Caucasian women. CONCLUSION: There was no association between level of estradiol and breast cancer. This is yet another disparity between women of African origin and the non Africans in high resourced countries. There is need to explore more to explain this disparity.

2-methoxyestradiol inhibits the anaphase-promoting complex and protein translation in human breast cancer cells
            (Bhati et al., 2007) Download
2-methoxyestradiol (2ME2), an estradiol metabolite with antiproliferative and antiangiogenic activities, is in phase I/II clinical trials for breast cancer. 2ME2 inhibits microtubule polymerization and causes cells to arrest in G2-M. The purpose of this study was to further elucidate the molecular mechanism of 2ME2. MDA-MB-435 breast cancer cells were treated with 2ME2 (2 micromol/L) or vehicle alone. RNA was extracted and genomic profiling was done using 22k Agilent microarrays. Expression Analysis Systematic Explorer was used to determine enrichment of Gene Ontology categories. Protein isolates were subjected to Western blot analysis. Protein synthesis was measured with a [35S]methionine pulse assay. An MDA-MB-435 cell line with two beta-tubulin mutations (2ME2R) was used to determine whether novel mechanisms were tubulin-dependent. Gene Ontology categories enriched include genes that regulate the mitotic spindle assembly checkpoint, apoptosis, and the cytosolic ribosome. The target of the mitotic spindle assembly checkpoint is the anaphase-promoting complex (APC). APC inhibition was confirmed by measuring protein levels of its targets securin and cyclin B1, which were increased in 2ME2-treated cells. Because gene expression in the cytosolic ribosome category was decreased, we evaluated whether 2ME2 decreases protein translation. This was confirmed with a pulse assay, which showed decreased isotope incorporation in 2ME2-treated cells, which was maintained in the tubulin-resistant 2ME2R cells. APC inhibition was not maintained in 2ME2R cells. 2ME2 induces tubulin-dependent cell cycle arrest through regulation of genes involved in the mitotic spindle assembly checkpoint, which results in inhibition of the APC and tubulin-independent inhibition of protein translation.


Lower-dose vs high-dose oral estradiol therapy of hormone receptor-positive, aromatase inhibitor-resistant advanced breast cancer: a phase 2 randomized study
            (Ellis et al., 2009) Download
CONTEXT: Estrogen deprivation therapy with aromatase inhibitors has been hypothesized to paradoxically sensitize hormone-receptor-positive breast cancer tumor cells to low-dose estradiol therapy. OBJECTIVE: To determine whether 6 mg of estradiol (daily) is a viable therapy for postmenopausal women with advanced aromatase inhibitor-resistant hormone receptor-positive breast cancer. DESIGN, SETTING, AND PATIENTS: A phase 2 randomized trial of 6 mg vs 30 mg of oral estradiol used daily (April 2004-February 2008 [enrollment closed]). Eligible patients (66 randomized) had metastatic breast cancer treated with an aromatase inhibitor with progression-free survival (> or = 24 wk) or relapse (after > or = 2 y) of adjuvant aromatase inhibitor use. Patients at high risk of estradiol-related adverse events were excluded. Patients were examined after 1 and 2 weeks for clinical and laboratory toxicities and flare reactions and thereafter every 4 weeks. Tumor radiological assessment occurred every 12 weeks. At least 1 measurable lesion or 4 measurable lesions (bone-only disease) were evaluated for tumor response. INTERVENTION: Randomization to receive 1 oral 2-mg generic estradiol tablet 3 times daily or five 2-mg tablets 3 times daily. MAIN OUTCOME MEASURES: Primary end point: clinical benefit rate (response plus stable disease at 24 weeks). Secondary outcomes: toxicity, progression-free survival, time to treatment failure, quality of life, and the predictive properties of the metabolic flare reaction detected by positron emission tomography/computed tomography with fluorodeoxyglucose F 18. RESULTS: The adverse event rate (> or = grade 3) in the 30-mg group (11/32 [34%]; 95% confidence interval [CI], 23%-47%) was higher than in the 6-mg group (4/34 [18%]; 95% CI, 5%-22%; P = .03). Clinical benefit rates were 9 of 32 (28%; 95% CI, 18%-41%) in the 30-mg group and 10 of 34 (29%; 95% CI, 19%-42%) in the 6-mg group. An estradiol-stimulated increase in fluorodeoxyglucose F 18 uptake (> or = 12% prospectively defined) was predictive of response (positive predictive value, 80%; 95% CI, 61%-92%). Seven patients with estradiol-sensitive disease were re-treated with aromatase inhibitors at estradiol progression, among which 2 had partial response and 1 had stable disease, suggesting resensitization to estrogen deprivation. CONCLUSIONS: In women with advanced breast cancer and acquired resistance to aromatase inhibitors, a daily dose of 6 mg of estradiol provided a similar clinical benefit rate as 30 mg, with fewer serious adverse events. The efficacy of treatment with the lower dose should be further examined in phase 3 clinical trials. TRIAL REGISTRATION: Identifier: NCT00324259.


Inhibition of GPR30 by estriol prevents growth stimulation of triple-negative breast cancer cells by 17β-estradiol.
            (Girgert et al., 2014) Download
BACKGROUND:  Due to the lack of ERα, triple negative breast cancers (TNBCs) are not susceptible to endocrine therapy using antiestrogens. However, the majority of TNBCs express the membrane bound estrogen receptor GPR30. We have recently shown that knock-down of GPR30 expression prevented growth stimulation of TNBC cell lines by 17β-estradiol. Now we analyzed whether specific inhibition of GPR30 represents a new option for therapy of TNBC. METHODS:  Growth of TNBC cells was assessed using Alamar-blue colorimetric assay. Activation of c-Src and EGF-receptor was assessed using Western blots. Expression of c-fos, cyclin D1 and aromatase was quantified by RT-PCR. Gα-specific signaling of GPR30 was analyzed by electrophoretic mobility shift assay. RESULTS:  HCC1806 cells showed the highest GPR30 expression, in HCC70 cells it was clearly lower, in MDA-MB-231 cells it was lowest. 10-8 M 17β-estradiol significantly increased proliferation of HCC1806 cells to 134 ± 12% of control (p < 0.01). Proliferation of HCC70 cells was slightly increased to 116 ± 8% of control. Estriol significantly reduced cell number of HCC1806 cells to 16 ± 12% (p < 0.01). Cell number of HCC70 cells and of MDA-MB-231 cells was reduced to 68 ± 25% and to 61 ± 10%, respectively.Activity of Src kinase increased to 150 ± 10% (p < 0.05) by 10-8 M 17β-estradiol treatment in HCC1806 and to 220 ± 20% in HCC70 cells (p < 0.01). Estriol treatment completely inhibited 17β-estradiol-induced p-src activation. Transactivation of EGF-receptor increased by estradiol treatment to 350% in HCC1806 and to 280% in HCC70 cells. Estriol completely suppressed EGF-receptor transactivation. c-fos expression increased to 260% and to 190%, respectively. Estriol reduced this induction to 160% (HCC1806) and below control in HCC70 cells. Cyclin D1 was induced to 290% (HCC1806) and 170% (HCC70) and completely inhibited by estriol. 17β-estradiol increased CREB-phosphorylation to 400%. Binding of phospho-CREB to a CRE of cyclin D1 was enhanced to 320%. CONCLUSION:  Specific pharmacological inhibition of GPR30 might become a promising targeted therapy for TNBC in future.

Roles for estrogen and progesterone in breast cancer prevention
            (Jerry, 2007) Download
Prevention has long been the holy grail of breast cancer research. The significant reduction in breast cancer risk afforded by a full-term pregnancy early in life suggests the great potential of preventive strategies. In contrast to the risks associated with prolonged exposures, exogenous estrogen and progesterone for short durations can mimic the protective effects of pregnancy in carcinogen-induced mammary tumor models. Rajkumar and coworkers have now demonstrated that these hormones protect mice from mammary tumors initiated by a spectrum of oncogenic alterations that are common in breast cancers. Although differences between rodent models and humans remain, the results reveal that exogenous estrogen and progesterone potently inhibit tumorigenesis through multiple pathways and establish a foundation for strategies to prevent breast cancer.

Paradoxical clinical effect of estrogen on breast cancer risk: a "new" biology of estrogen-induced apoptosis.
            (Jordan and Ford, 2011) Download
Administration of estrogen replacement therapy (ERT) decreases the incidence of breast cancer, as shown in a double-blind, placebo-controlled randomized trial of the Women's Health Initiative (WHI) in 10,739 postmenopausal women with a prior hysterectomy. Although paradoxical because estrogen is recognized to stimulate breast cancer growth, laboratory data support a mechanism of estrogen-induced apoptosis under the correct environmental circumstances. Long-term antiestrogen treatment or estrogen deprivation causes the eventual development and evolution of antihormone resistance. Cell populations emerge with a vulnerability, as estrogen is no longer a survival signal but is an apoptotic trigger. The antitumor effect of ERT in estrogen-deprived postmenopausal women is consistent with laboratory models.

2-Methoxyestradiol suppresses microtubule dynamics and arrests mitosis without depolymerizing microtubules
            (Kamath et al., 2006) Download
2-Methoxyestradiol (2ME2), a metabolite of estradiol-17beta, is a novel antimitotic and antiangiogenic drug candidate in phase I and II clinical trials for the treatment of a broad range of tumor types. 2ME2 binds to tubulin at or near the colchicine site and inhibits the polymerization of tubulin in vitro, suggesting that it may work by interfering with normal microtubule function. However, the role of microtubule depolymerization in its antitumor mechanism of action has been controversial. To determine the mechanism by which 2ME2 induces mitotic arrest, we analyzed its effects on microtubule polymerization in vitro and its effects on dynamic instability both in vitro and in living MCF7 cells. In vitro, 2ME2 (5-100 micromol/L) inhibited assembly of purified tubulin in a concentration-dependent manner, with maximal inhibition (60%) at 200 micromol/L 2ME2. However, with microtubule-associated protein-containing microtubules, significantly higher 2ME2 concentrations were required to depolymerize microtubules, and polymer mass was reduced by only 13% at 500 micromol/L 2ME2. In vitro, dynamic instability was inhibited at lower concentrations. Specifically, 4 micromol/L 2ME2 reduced the mean growth rate by 17% and dynamicity by 27%. In living interphase MCF7 cells at the IC50 for mitotic arrest (1.2 micromol/L), 2ME2 significantly suppressed the mean microtubule growth rate, duration and length, and the overall dynamicity, consistent with its effects in vitro, and without any observable depolymerization of microtubules. Taken together, the results suggest that the major mechanism of mitotic arrest at the lowest effective concentrations of 2ME2 is suppression of microtubule dynamics rather than microtubule depolymerization per se.

2-methoxyestradiol up-regulates death receptor 5 and induces apoptosis through activation of the extrinsic pathway
            (LaVallee et al., 2003) Download
2-Methoxyestradiol (2ME2), a natural metabolite of estradiol, is a potent antitumor and antiangiogenic agent. In vitro, 2ME2 inhibits the proliferation of a wide variety of cell lines and primary cultures, and in numerous models in vivo, it has been shown to be an effective inhibitor of tumor growth and angiogenesis. 2ME2 is currently in several Phase I and Phase II clinical trials under the name Panzem. Although various molecular targets have been proposed for this compound, the mechanism by which 2ME2 exerts its effects is still uncertain. This study shows that 2ME2 uses the extrinsic pathway for induction of apoptosis. 2ME2 treatment results in up-regulation of death receptor 5 (DR5) protein expression in vitro and in vivo and renders cells more sensitive to the cytotoxic activities of the DR5 ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). 2ME2-induced apoptosis requires caspase activation and kinetic studies show the sequential activation of caspase-8, caspase-9, and caspase-3. Blockage of death receptor signaling by expression of dominant-negative Fas-associated death domain severely attenuates the ability of 2ME2 to induce apoptosis. Because 2ME2 administration has not manifested dose-limiting toxicity in the clinic, DR5 expression may serve as a surrogate marker for biological response.

Reduced estriol excretion in patients with breast cancer prior to endocrine therapy.
            (Lemon et al., 1966) Download
The urinary estriol excretion quotient = estriol ÷ (estrone + estradiol) was measured in 30 patients with breast cancer (median 0.5 or 0.8) and 30 controls (median 1).

Breast cancer risk in postmenopausal women using estrogen-only therapy
            (Lyytinen et al., 2006) Download
OBJECTIVE: To evaluate whether the risk of estrogen-only therapy on breast cancer varies by dose, constituent, and route of administration. METHODS: All Finnish women older than age 50 years using oral or transdermal estradiol (n=84,729), oral estriol (n=7,941), or vaginal estrogens (n=18,314) for at least 6 months during 1994-2001 were identified from the national medical reimbursement register. They were followed for breast cancer with the aid of the Finnish Cancer Registry to the end of 2002. RESULTS: Altogether, 2,171 women with breast cancer were identified. The standardized incidence ratio of breast cancer with systemic estradiol for less than 5 years was 0.93 (95% confidence interval 0.80-1.04), and for estradiol use for 5 years or more, 1.44 (1.29-1.59). Oral and transdermal estradiol was accompanied by a similar risk of breast cancer. The risk was most prominent with the dose greater than 1.9 mg/d orally; whereas the risk associated with transdermal route was not dose-dependent. The standardized incidence ratio for the lobular type of breast cancer (1.58) was slightly higher than that for the ductal type (1.36). The use of estradiol was associated with both localized breast cancer (1.45; 1.26-1.66) and cancer spread to regional nodes (1.35; 1.09-1.65). The incidence of carcinoma in situ (n=32) was increased (2.43; 1.66-3.42) among estradiol users. CONCLUSION: Estradiol for 5 years or more, either orally or transdermally, means 2-3 extra cases of breast cancer per 1,000 women who are followed for 10 years. Oral estradiol use for less than 5 years, oral estriol, or vaginal estrogens were not associated with a risk of breast cancer. LEVEL OF EVIDENCE: II-2.

Estrogen-like activity of metals in MCF-7 breast cancer cells.
            (Martin et al., 2003) Download
The ability of metals to activate estrogen receptor-alpha (ERalpha) was measured in the human breast cancer cell line, MCF-7. Similar to estradiol, treatment of cells with the divalent metals copper, cobalt, nickel, lead, mercury, tin, and chromium or with the metal anion vanadate stimulated cell proliferation; by d 6, there was a 2- to 5-fold increase in cell number. The metals also decreased the concentration of ERalpha protein and mRNA by 40-60% and induced expression of the estrogen-regulated genes progesterone receptor and pS2 by1.6- to 4-fold. Furthermore, there was a 2- to 4-fold increase in chloramphenicol acetyltransferase activity after treatment with the metals in COS-1 cells transiently cotransfected with the wild-type receptor and an estrogen-responsive chloramphenicol acetyltransferase reporter gene. The ability of the metals to alter gene expression was blocked by an antiestrogen, suggesting that the activity of these compounds is mediated by ERalpha. In binding assays the metals blocked the binding of estradiol to the receptor without altering the apparent binding affinity of the hormone (K(d) = 10(-10) M). Scatchard analysis employing either recombinant ERalpha or extracts from MCF-7 cells demonstrated that (57)Co and (63)Ni bind to ERalpha with equilibrium dissociation constants of 3 and 9.5 x 10(-9) and 2 and 7 x 10(-9) M, respectively. The ability of the metals to activate a chimeric receptor containing the hormone-binding domain of ERalpha suggests that their effects are mediated through the hormone-binding domain. Mutational analysis identified amino acids C381, C447, E523, H524, N532, and D538 as potential interaction sites, suggesting that divalent metals and metal anions activate ERalpha through the formation of a complex within the hormone-binding domain of the receptor.


Prevention of mammary carcinogenesis by short-term estrogen and progestin treatments.
            (Rajkumar et al., 2004) Download
INTRODUCTION:  Women who have undergone a full-term pregnancy before the age of 20 have one-half the risk of developing breast cancer compared with women who have never gone through a full-term pregnancy. This protective effect is observed universally among women of all ethnic groups. Parity in rats and mice also protects them against chemically induced mammary carcinogenesis. METHODS:  Seven-week-old virgin Lewis rats were given N-methyl-N-nitrosourea. Two weeks later the rats were treated with natural or synthetic estrogens and progestins for 7-21 days by subcutaneous implantation of silastic capsules. RESULTS:  In our current experiment, we demonstrate that short-term sustained exposure to natural or synthetic estrogens along with progestins is effective in preventing mammary carcinogenesis in rats. Treatment with 30 mg estriol plus 30 mg progesterone for 3 weeks significantly reduced the incidence of mammary cancer. Short-term exposure to ethynyl estradiol plus megesterol acetate or norethindrone was effective in decreasing the incidence of mammary cancers. Tamoxifen plus progesterone treatment for 3 weeks was able to confer only a transient protection from mammary carcinogenesis, while 2-methoxy estradiol plus progesterone was effective in conferring protection against mammary cancers. CONCLUSIONS:  The data obtained in the present study demonstrate that, in nulliparous rats, long-term protection against mammary carcinogenesis can be achieved by short-term treatments with natural or synthetic estrogen and progesterone combinations.

The Western dietary pattern is associated with increased serum concentrations of free estradiol in postmenopausal women: implications for breast cancer prevention.
            (Sánchez-Zamorano et al., 2016) Download
Little is known about the possible influence of food consumption on the serum concentrations of endogenous sex hormones in postmenopausal women. We evaluated the relationships of the Western dietary pattern with serum concentrations of free estradiol and testosterone of postmenopausal women to test the hypothesis that a highly Western dietary pattern is associated with high serum concentrations of these hormones. We used data from a representative subsample of 305 women from the control group of a population-based case-control study conducted in Mexico from 2004 to 2007. A Western dietary pattern index value was compared with log natural serum concentrations of testosterone and estradiol using multiple linear regression models. The median values of serum concentrations of free estradiol and testosterone were 0.26 pg/mL (interquartile range, 0.14-0.43) and 0.40 pg/mL (interquartile range, 0.30-0.70), respectively. A multiple linear regression model showed that for each unit increase in the Western dietary pattern index, there was a 16.2% increase in the serum concentrations of free estradiol (β=0.15; 95% confidence interval [CI], 0.01-0.29); for each additional serving per week of chicken eggs, the increase was 31.0% (β=0.27; 95% CI, 0.106-0.441); for each additional serving per week of red meat, the increase was 64.9% (β=0.50; 95% CI, 0.01-1.01). There was no relationship found between dietary patterns and serum concentrations of free testosterone. The present findings suggest that intake of a Western diet, particularly of chicken eggs and meat, increases serum concentrations of free estradiol; these results have implications for breast cancer prevention.

Mimicking pregnancy as a strategy for breast cancer prevention.
            (Santucci-Pereira et al., 2013) Download
Pregnancy and its effects on breast cancer risk have been widely investigated; there is consensus among researchers that early pregnancy confers protection against breast cancer later in life, whereas nulliparity and late-age parity have been associated with increased risk of developing breast cancer. The answer to the question of how pregnancy reduces breast cancer risk has been elusive; however, pregnancy, like breast cancer, is a similar hormone-dependent entity under direct control of estrogen, progesterone and, of particular importance, human chorionic gonadotropin (hCG). In this report, we emphasize the main changes, previously described by our laboratory, in morphology and gene expression levels of the mammary gland of Sprague-Dawley rats exposed to known cancer-preventative conditions (pregnancy, hCG and progesterone + estrogen). In addition, we postulate a protective mechanism induced by hCG that could reduce the cell's potential to be transformed by carcinogens.

Prevention of breast cancer by recapitulation of pregnancy hormone levels.
            (Tonetti, 2004) Download
At the present time, the only approved method of breast cancer prevention is use of the selective estrogen receptor modulator (SERM) tamoxifen. Many breast cancers are driven to grow by estrogen, and tamoxifen exploits this by blocking estrogen action at the estrogen receptor. A counter-intuitive and controversial approach to breast cancer prevention is administration of estrogen and progestin at an early age to achieve pregnancy levels. This approach is supported by the fact that breast cancer incidence is halved by early (< or = 20 years of age) full-term pregnancy. Moreover, it has been demonstrated in rodent models that mimicking the hormonal milieu can effectively prevent carcinogen-induced mammary cancer. In this issue of Breast Cancer Research Rajkumar and colleagues use the rodent model to further define the timing and type of hormonal therapy that is effective in preventing mammary carcinogenesis. Clearly, application of this approach in humans may be difficult, but the potential benefit is intriguing.


Estrogen's dual nature? Studies highlight effects on breast cancer.
            (Twombly, 2011) Download
The story of estrogen’s role in breast cancer is starting to look like Dr. Jekyll and Mr. Hyde. A spate of recent studies demonstrates that the hormone - long known to fuel growth of most breast tumors - may actually be effective in treating breast cancer, or even preventing it.

Estrogen carcinogenesis in breast cancer.
            (Yager and Davidson, 2006) Download
Studies of breast cancer have consistently found an increased risk associated with elevated blood levels of endogenous estrogen, clinical indicators of persistently elevated blood estrogen levels, and exposure to exogenous estrogen plus progestin through hormone-replacement therapy and the use of oral contraceptives.



American, College of Obstetricians and Gynecologists’ Committee on Gynecologic Practice and R Farrell (2016), ‘ACOG Committee Opinion No. 659: The Use of Vaginal Estrogen in Women With a History of Estrogen-Dependent Breast Cancer.’, Obstet Gynecol, 127 (3), e93-6. PubMed: 26901334
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Bhati, R., et al. (2007), ‘2-methoxyestradiol inhibits the anaphase-promoting complex and protein translation in human breast cancer cells’, Cancer Res, 67 (2), 702-8. PubMed: 17234781
Ellis, M. J., et al. (2009), ‘Lower-dose vs high-dose oral estradiol therapy of hormone receptor-positive, aromatase inhibitor-resistant advanced breast cancer: a phase 2 randomized study’, Jama, 302 (7), 774-80. PubMed: 19690310
Girgert, R, G Emons, and C Gründker (2014), ‘Inhibition of GPR30 by estriol prevents growth stimulation of triple-negative breast cancer cells by 17β-estradiol.’, BMC Cancer, 14 935. PubMed: 25496649
Jerry, D. J. (2007), ‘Roles for estrogen and progesterone in breast cancer prevention’, Breast Cancer Res, 9 (2), 102. PubMed: 17381827
Jordan, VC and LG Ford (2011), ‘Paradoxical clinical effect of estrogen on breast cancer risk: a “new” biology of estrogen-induced apoptosis.’, Cancer Prev Res (Phila), 4 (5), 633-37. PubMed: 21478501
Kamath, K., et al. (2006), ‘2-Methoxyestradiol suppresses microtubule dynamics and arrests mitosis without depolymerizing microtubules’, Mol Cancer Ther, 5 (9), 2225-33. PubMed: 16985056
LaVallee, T. M., et al. (2003), ‘2-methoxyestradiol up-regulates death receptor 5 and induces apoptosis through activation of the extrinsic pathway’, Cancer Res, 63 (2), 468-75. PubMed: 12543804
Lemon, HM, et al. (1966), ‘Reduced estriol excretion in patients with breast cancer prior to endocrine therapy.’, JAMA, 196 (13), 1128-36. PubMed: 5952514
Lyytinen, H., E. Pukkala, and O. Ylikorkala (2006), ‘Breast cancer risk in postmenopausal women using estrogen-only therapy’, Obstet Gynecol, 108 (6), 1354-60. PubMed: 17138766
Martin, MB, et al. (2003), ‘Estrogen-like activity of metals in MCF-7 breast cancer cells.’, Endocrinology, 144 (6), 2425-36. PubMed: 12746304
Rajkumar, L, et al. (2004), ‘Prevention of mammary carcinogenesis by short-term estrogen and progestin treatments.’, Breast Cancer Res, 6 (1), R31-7. PubMed: 14680498
Sánchez-Zamorano, LM, et al. (2016), ‘The Western dietary pattern is associated with increased serum concentrations of free estradiol in postmenopausal women: implications for breast cancer prevention.’, Nutr Res, 36 (8), 845-54. PubMed: 27440539
Santucci-Pereira, J, et al. (2013), ‘Mimicking pregnancy as a strategy for breast cancer prevention.’, Breast Cancer Manag, 2 (4), 283-94. PubMed: 24738009
Tonetti, DA (2004), ‘Prevention of breast cancer by recapitulation of pregnancy hormone levels.’, Breast Cancer Res, 6 (1), E8. PubMed: 14680493
Twombly, R (2011), ‘Estrogen’s dual nature? Studies highlight effects on breast cancer.’, J Natl Cancer Inst, 103 (12), 920-21. PubMed: 21693756
Yager, JD and NE Davidson (2006), ‘Estrogen carcinogenesis in breast cancer.’, N Engl J Med, 354 (3), 270-82. PubMed: 16421368