Elevated Luteinizing Hormone in Serum, Breast Cancer Tissue, and Normal Breast Tissue from Breast Cancer Patients

Silva, Elvio G.; Mistry, Dinu; Li, Donghui; Kuerer, Henry Mark; Atkinson, E. Neely; Lopez, Abel N.; Shannon, Rhonda L.; Hortobágyi, Gabriel N.

doi:10.1023/a:1020528722842

Cited by 13 publications

(5 citation statements)

References 11 publications

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“…There is evidence that breast cancer tissues and cells synthesize hCG and LH, suggesting paracrine and autocrine actions of these hormones (53)(54)(55). These findings suggest that strategies which can increase the local production of these hormones may work in a fight against this malignancy.…”

Section: Discussionmentioning

confidence: 97%

Human Chorionic Gonadotropin Decreases Proliferation and Invasion of Breast Cancer MCF-7 Cells by Inhibiting NF-κB and AP-1 Activation

Rao

Manna

et al. 2004

Journal of Biological Chemistry

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The epidemiological data suggest that breast cancer risk decreases in women who complete full-term pregnancy at a young age. Studies on a rat breast cancer model indicate that human chorionic gonadotropin (hCG), a hormone that is present in very high levels during pregnancy, could be responsible for this decrease. These findings, as well as those demonstrating the presence of functional luteinizing hormone (LH)/ hCG receptors in human breast cells, prompted us to investigate the anti-proliferative and anti-invasive effects of hCG in human breast cancer MCF-7 cells by down-regulating NF-B and AP-1 transcription factors. Treatment of MCF-7 cells with highly purified hCG resulted in a modest dose-dependent and hormone-specific decrease in cell proliferation. hCG treatment also decreased cell invasion, which was more dramatic than the decrease in cell proliferation. These hCG actions were abrogated when receptor synthesis was inhibited by treatment with antisense hCG/LH receptor phosphorothioate oligodeoxynucleotide. hCG treatment prevented the tumor necrosis factor-dependent NF-B and AP-1 activation, which paralleled a decrease in the phosphorylation and degradation of IB␣. The findings that hCG treatment increased cAMP synthesis and activated cAMP-dependent protein kinase, dibutyryl cAMP mimicked hCG in preventing NF-B activation, and dideoxyadenosine, an adenylate cyclase inhibitor, prevented the hCG effect on NF-B suggested that the hCG actions are mediated via the cAMP-dependent protein kinase A signaling pathway. In summary, our results demonstrate that hCG has anti-proliferative and antiinvasive effects in MCF-7 cells by down-regulating NF-B and AP-1. These findings support the premise that hCG could be responsible for the pregnancy-induced protection against breast cancer in women.

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Section: Discussionmentioning

confidence: 97%

Human Chorionic Gonadotropin Decreases Proliferation and Invasion of Breast Cancer MCF-7 Cells by Inhibiting NF-κB and AP-1 Activation

Rao

Manna

et al. 2004

Journal of Biological Chemistry

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“…Serum IGF-I:IGFBP-3 ratio and non-sex hormone binding globulin bound levels of estradiol, as well as free testosterone have been reported as risk factors for breast cancer (19,47). LH, which stimulates the conversion of cholesterol to pregnenolone as the first step in steroidogenesis, has been found to be elevated in breast cancers (48). High levels of sex hormone binding globulin, which may result in decreased levels of bioavailable estradiol and testosterone, are associated with reduced breast cancer risk (20).…”

Section: Discussionmentioning

confidence: 99%

Breast cancer chemoprevention Phase IB evaluation of biomarker modulation by arzoxifene, a third generation selective estrogen receptor modulator

Fabian

Kimler

Anderson

et al. 2004

JCO

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Purpose: Arzoxifene, a new selective estrogen receptor modulator with strong breast antiestrogen activity and absence of uterine agonist activity, was explored as a potential chemoprevention agent. We performed a multi-institutional evaluation of arzoxifene in women with newly diagnosed ductal carcinoma in situ or T1/T2 invasive cancer.Experimental Design: In a Phase IA trial, 50 pre-or postmenopausal women were randomized to 10, 20, or 50 mg of arzoxifene daily in the interval between biopsy and re-excision or were enrolled as no-treatment controls. In a Phase IB trial, 76 postmenopausal women were randomized to 20 mg of arzoxifene versus matched placebo. Serum specimens collected at entry and at re-excision were assayed for various hormones and growth factors. Tissue from biopsies (estrogen receptor ؉ and/or progesterone receptor ؉) and re-excision specimens was evaluated immunohistochemically for proliferation (Ki-67 by MIB-1 and proliferating cell nuclear antigen) and other biomarkers.Results: In both trials, increases in serum sex hormone binding globulin were noted, as were decreases in insulinlike growth factor (IGF)-I and the IGF-I:IGF binding protein-3 ratio (P < 0.007 versus control/placebo). For 45 evaluable women in Phase IA, decreases in proliferation indices were more prevalent for arzoxifene (particularly 20 mg) than for controls. For 58 evaluable women in Phase IB, a decrease in estrogen receptor expression for arzoxifene was observed compared with no change with placebo (P ‫؍‬ 0.0068). However, decreases in proliferation indices for arzoxifene were not statistically different from placebo, perhaps due to a confounding effect of stopping hormone replacement therapy before entry.Conclusion: Given the favorable side effect profile and the biomarker modulations reported here, arzoxifene remains a reasonable candidate for additional study as a breast cancer chemoprevention agent.

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“…Alternatively, it may be that high luteinsing hormone (LH) or follicle-stimulating hormone (FSH) concentrations, which peak prior to ovulation, are responsible for poorer rates of disease free and overall survival independent of estrogen and progesterone concentrations. FSH and LH can increase the invasive ability of breast cancer cells in vitro and in vivo (39,40); and in breast cancer patients LH expression is increased in breast tumour tissue compared to normal breast tissue (41). However, the roles of LH and FSH in breast cancer initiation and progression are not well defined, and how they may contribute to metastasis warrants further investigation.…”

Section: Classification Of Menstrual Cycle Usingmentioning

confidence: 99%

Timing of breast cancer surgery during the menstrual cycle‑is there an optimal time of the month? (Review)

et al. 2020

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An intriguing relationship between menstrual cycle phase at the time of breast cancer surgery and clinical outcomes was first proposed in the late 1980s. Despite a number of clinical studies conducted to address this, as well as meta-analyses and systematic reviews, there remains significant controversy surrounding the effect of menstrual cycle phase at time of surgery on the prognosis of premenopausal breast cancer. While some studies have suggested that surgery performed during the luteal phase results in the most favourable outcome, other studies report the follicular phase is more favourable, and others show no association. Given the conflicting results, there remains insufficient evidence to determine whether there is an optimal time of the month to perform surgery. This issue has dogged breast cancer surgery for decades; knowledge of an optimal time of the month to conduct surgery would be a simple approach to improving patient outcomes. This review explores the potential biological mechanisms through which the hormonal milieu might contribute to differences in prognosis, and why clinical findings are so variable. It is concluded that a significant problem with current clinical research is the lack of insight from mechanistic studies. While there are a number of plausible biological mechanisms that could lead to altered survival, supporting evidence is limited. There are also variable approaches to defining the menstrual cycle phase and hormone receptor status of the tumour and few studies controlled for prognostic factors such as tumour size and stage, or addressed the impact of adjuvant treatments. Elucidation of the specific confounding factors, as well as biological mechanistic pathways that could explain the potential relationship between timing of surgery and survival, will greatly assist in designing robust well-controlled prospective clinical studies to evaluate this paradigm.

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Elevated Luteinizing Hormone in Serum, Breast Cancer Tissue, and Normal Breast Tissue from Breast Cancer Patients

Cited by 13 publications

References 11 publications

Human Chorionic Gonadotropin Decreases Proliferation and Invasion of Breast Cancer MCF-7 Cells by Inhibiting NF-κB and AP-1 Activation

Human Chorionic Gonadotropin Decreases Proliferation and Invasion of Breast Cancer MCF-7 Cells by Inhibiting NF-κB and AP-1 Activation

Breast cancer chemoprevention Phase IB evaluation of biomarker modulation by arzoxifene, a third generation selective estrogen receptor modulator

Timing of breast cancer surgery during the menstrual cycle‑is there an optimal time of the month? (Review)

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