Management of Breast Cancer Survivors by Gynecologists.

Breast cancer patients commonly present to their OBGYN during the process of diagnosis and treatment of breast cancer both for specific gynecologic needs and for primary care follow up. These patients require counseling on contraception, hormone use, and fertility at diagnosis. During treatment and survivorship, patients will face a variety of side effects from treatments leading to vasomotor symptoms, vulvovaginal discomfort, sexual dysfunction, osteoporosis, and vaginal bleeding. This chapters aims to enlighten providers on the unique range of issues a gynecologist may face when caring for breast cancer patients.

Patient and provider factors associated with the noninitiation of tamoxifen for young women at high-risk for the development of breast cancer.

We sought to identify factors associated with disparities in tamoxifen utilization among young patients at high-risk for developing breast cancer. We identified 67 premenopausal, high-risk women age 35-45, without surgical prophylaxis, who did not initiate tamoxifen. Factors associated with noninitiation were examined. About 37% of patients had no documented provider-based discussion regarding initiation. Type of high-risk diagnosis was the only factor associated with a provider-based discussion (P = .03). For patients offered tamoxifen, primary reasons for noninitiation were perceived minimal benefit (66.7%), fertility concerns (16.7%), and concerns about side effects (7.1%). Implementation of comprehensive educational strategies regarding the benefits of tamoxifen should be facilitated to improve initiation among young high-risk patients.

When Should Prophylactic Oophorectomy Be Recommended at the Time of Elective Hysterectomy?

Gynecologists are frequently confronted with the decision of when to recommend oophorectomy at the time of an elective hysterectomy. When deciding if oophorectomy should be recommended, first a careful history and risk assessment must be performed to determine if a patient is a candidate for a risk-reducing oophorectomy. If the patient does not have a hereditary ovarian cancer risk, then it is recommended the surgeon carefully consider the implications of ovarian removal on the health of their patient. This review covers the potential benefits and risks of prophylactic oophorectomy and offers a decision aid for when to recommend this procedure.

Health Disparities in Ovarian Cancer: Report From the Ovarian Cancer Evidence Review Conference.

Health disparity, defined by the Centers for Disease Control and Prevention (CDC) as "preventable differences in the burden of disease, injury, violence, or opportunities to achieve optimal health that are experienced by socially disadvantaged populations," is seen across multiple diseases. We conducted an evidence review of health disparities and inequities and their mitigation strategies related to ovarian cancer as part of a CDC-sponsored project to develop educational materials for clinicians on the prevention and early diagnosis of gynecologic cancers. Our review found profound disparities in outcomes such as survival, treatment, and stage at diagnosis by factors such as race and ethnicity, insurance, socioeconomic status, and geographic location. We found little direct evidence on mitigation strategies. Studies support equivalent response to equivalent treatment between groups, suggesting that adherence to National Comprehensive Cancer Network guidelines can at least partially mitigate some of the differences.

Executive Summary of the Ovarian Cancer Evidence Review Conference.

The Centers for Disease Control and Prevention awarded funding to the American College of Obstetricians and Gynecologists to develop educational materials for clinicians on gynecologic cancers. The American College of Obstetricians and Gynecologists convened a panel of experts in evidence review from the Society for Academic Specialists in General Obstetrics and Gynecology and content experts from the Society of Gynecologic Oncology to review relevant literature, best practices, and existing practice guidelines as a first step toward developing evidence-based educational materials for women's health care clinicians about ovarian cancer. Panel members conducted structured literature reviews, which were then reviewed by other panel members and discussed at a virtual meeting of stakeholder professional and patient advocacy organizations in February 2022. This article is the executive summary of the relevant literature and existing recommendations to guide clinicians in the prevention, early diagnosis, and special considerations of ovarian cancer. Substantive knowledge gaps are noted and summarized to provide guidance for future research.

Phosphorylation of elongation factor-2 kinase differentially regulates the enzyme's stability under stress conditions.

Eukaryotic elongation factor-2 kinase (eEF-2K) is a Ca(2+)/calmodulin-dependent enzyme that negatively regulates protein synthesis. eEF-2K has been shown to be up-regulated in cancer, and to play an important role in cell survival through inhibition of protein synthesis. Post-translational modification of protein synthesis machinery is important for its regulation and could be critical for survival of cancer cells encountering stress. The purpose of our study was to examine the regulation of eEF-2K during stress with a focus on the roles of phosphorylation in determining the stability of eEF-2K. We found that stress conditions (nutrient deprivation and hypoxia) increase eEF-2K protein. mRNA levels are only transiently increased and shortly return to normal, while eEF-2K protein levels continue to increase after further exposure to stress. A seemingly paradoxical decrease in eEF-2K stability was found when glioma cells were subjected to stress despite increased protein expression. We further demonstrated that phosphorylation of eEF-2K differentially affects the enzyme's turnover under both normal and stress conditions, as evidenced by the different half-lives of phosphorylation-defective mutants of eEF-2K. We further found that the eEF-2K site (Ser398) phosphorylated by AMPK is pivotal to the protein's stability, as the half-life of S398A mutant increases to greater than 24h under both normal and stress conditions. These data indicate that eEF-2K is regulated at multiple levels with phosphorylation playing a critical role in the enzyme's turnover under stressful conditions. The complexity of eEF-2K phosphorylation highlights the intricacies of protein synthesis control during cellular stress.

Cancer genetics and breast cancer.

The risk of developing breast cancer is multifactorial and, at times, modifiable. However, the risk imposed by family history and hereditary pathogenic variants in a person's genetic code is, at present, an important fixed variable. Therefore, it is imperative to identify patients at risk for hereditary breast cancer and to understand the current evidence-based approach to the management of that risk. This chapter focuses on how genes play a role in breast cancer risk, why certain genes are commonly involved in hereditary breast cancer, and what are the specific genes and genetic syndromes that put patients at risk for breast cancer. Hereditary cancer susceptibility syndromes, including Hereditary Breast and Ovarian Cancer Syndrome (HBOC - BRCA1/2), Cowden Syndrome (CS - PTEN), Li-Fraumeni Syndrome (LFS - TP53), Peutz-Jegher Syndrome (PJS - STK11), Neurofibromatosis Type 1 (NF1), and Diffuse Hereditary Gastric Cancer Syndrome (CDH1) will be discussed along with individual genes not associated with a particular syndrome (ATM, BARD1, CHEK2, and PALB2).

Health Disparities in Uterine Cancer: Report From the Uterine Cancer Evidence Review Conference.

The Centers for Disease Control and Prevention recognized the need for educational materials for clinicians on the prevention and early diagnosis of gynecologic cancers. The American College of Obstetricians and Gynecologists convened a panel of experts in evidence review from the Society for Academic Specialists in General Obstetrics and Gynecology and content experts from the Society of Gynecologic Oncology to review relevant literature, best practices, and existing practice guidelines for the development of evidence-based educational materials for women's health care clinicians about uterine cancer. This article is the evidence summary of the literature review of health disparities and inequities related to uterine cancer. Substantive knowledge gaps are noted and summarized to provide guidance for future research.

Executive Summary of the Uterine Cancer Evidence Review Conference.

The Centers for Disease Control and Prevention recognized the need for educational materials for clinicians on the prevention and early diagnosis of gynecologic cancers. The American College of Obstetricians and Gynecologists convened a panel of experts in evidence review from the Society for Academic Specialists in General Obstetrics and Gynecology and content experts from the Society of Gynecologic Oncology to review relevant literature, best practices, and existing practice guidelines as a first step toward developing evidence-based educational materials for women's health care clinicians about uterine cancer. Panel members conducted structured literature reviews, which were then reviewed by other panel members and discussed at a virtual meeting of stakeholder professional and patient advocacy organizations in January 2021. This article is the evidence summary of the relevant literature and existing recommendations to guide clinicians in the prevention, early diagnosis, and special considerations of uterine cancer. Substantive knowledge gaps are noted and summarized to provide guidance for future research.

Inhibition of eEF-2 kinase sensitizes human glioma cells to TRAIL and down-regulates Bcl-xL expression.

Elongation factor-2 kinase (eEF-2 kinase, also known as calmodulin-dependent protein kinase III), is a unique calcium/calmodulin-dependent enzyme that inhibits protein synthesis by phosphorylating and inactivating elongation factor-2 (eEF-2). We previously reported that expression/activity of eEF-2 kinase was up-regulated in several types of malignancies including Gliomas, and was associated with response of tumor cells to certain therapeutic stress. In the current study, we sought to determine whether eEF-2 kinase expression affected sensitivity of glioma cells to treatment with tumor the necrosis factor-related apoptosis-inducing ligand (TRAIL), a targeted therapy able to induce apoptosis in cancer cells but causes no toxicity in most normal cells. We found that inhibition of eEF-2 kinase by RNA interference (RNAi) or by a pharmacological inhibitor (NH125) enhanced TRAIL-induced apoptosis in the human glioma cells, as evidenced by an increase in apoptosis in the tumor cells treated with eEF-2 kinase siRNA or the eEF-2 kinase inhibitor. We further demonstrated that sensitization of tumor cells to TRAIL was accompanied by a down-regulation of the anti-apoptotic protein, Bcl-xL, and that overexpression of Bcl-xL could abrogate the sensitizing effect of inhibiting eEF-2 kinase on TRAIL. The results of this study may help devise a new therapeutic strategy for enhancing the efficacy of TRAIL against malignant glioma by targeting eEF-2 kinase.

Integrated regulation of autophagy and apoptosis by EEF2K controls cellular fate and modulates the efficacy of curcumin and velcade against tumor cells.

Endoplasmic reticulum (ER) stress induces both autophagy and apoptosis yet the molecular mechanisms and pathways underlying the regulation of these two cellular processes in cells undergoing ER stress remain less clear. We report here that eukaryotic elongation factor-2 kinase (EEF2K) is a critical controller of the ER stress-induced autophagy and apoptosis in tumor cells. DDIT4, a stress-induced protein, was required for transducing the signal for activation of EEF2K under ER stress. We further showed that phosphorylation of EEF2K at Ser398 was essential for induction of autophagy, while phosphorylation of the kinase at Ser366 and Ser78 exerted an inhibitory effect on autophagy. Suppression of the ER stress-activated autophagy via silencing of EEF2K aggravated ER stress and promoted apoptotic cell death in tumor cells. Moreover, inhibiting EEF2K by either RNAi or NH125, a small molecule inhibitor of the enzyme, rendered tumor cells more sensitive to curcumin and velcade, two anticancer agents that possess ER stress-inducing action. Our study indicated that the DDIT4-EEF2K pathway was essential for inducing autophagy and for determining the fate of tumor cells under ER stress, and suggested that inhibiting the EEF2K-mediated autophagy can deteriorate ER stress and lead to a greater apoptotic response, thereby potentiating the efficacy of the ER stress-inducing agents against cancer.

Identification of Sirtuin 3, a mitochondrial protein deacetylase, as a new contributor to tamoxifen resistance in breast cancer cells.

The current study reports a previously unappreciated role of Sirtuin 3 (SIRT3), a mitochondrial protein deacetylase, in altering sensitivity of breast cancer cells to tamoxifen (Tam), a commonly used anti-estrogen agent. We showed that SIRT3 was significantly up-regulated at both mRNA and protein levels in the Tam-resistance human breast cancer cell line MTR-3, which was derived from MCF-7 line by continuous selective culture in the presence of 1µM of Tam for two years. We further demonstrated that SIRT3 was rapidly up-regulated in the sensitive MCF-7 cells following exposure to Tam. Transfection of MCF-7 cells with a SIRT3 expression plasmid decreased cellular sensitivity to Tam and blocked the Tam-induced apoptosis. Furthermore, silencing of SIRT3 expression in MTR-3 cells sensitized the resistant cells to Tam and enhanced apoptotic cell death. MTR-3 cells with silencing of SIRT3 expression showed increases in the mitochondrial content of ERß, ROS level and apoptosis. These results not only uncovered a new role for SIRT3 in cancer but also identified this mitochondrial protein deacetylase as a previously unrecognized factor that participates in regulation of Tam sensitivity in breast cancer cells. Thus, SIRT3 might be considered as a potential target for overcoming Tam resistance in treatment of breast cancer.

Rational incorporation of selenium into temozolomide elicits superior antitumor activity associated with both apoptotic and autophagic cell death.

BACKGROUND: The DNA alkylating agent temozolomide (TMZ) is widely used in the treatment of human malignancies such as glioma and melanoma. On the basis of previous structure-activity studies, we recently synthesized a new TMZ selenium analog by rationally introducing an N-ethylselenocyanate extension to the amide functionality in TMZ structure. PRINCIPAL FINDINGS: This TMZ-Se analog showed a superior cytotoxicity to TMZ in human glioma and melanoma cells and a more potent tumor-inhibiting activity than TMZ in mouse glioma and melanoma xenograft model. TMZ-Se was also effective against a TMZ-resistant glioma cell line. To explore the mechanism underlying the superior antitumor activity of TMZ-Se, we compared the effects of TMZ and TMZ-Se on apoptosis and autophagy. Apoptosis was significantly increased in tumor cells treated with TMZ-Se in comparison to those treated with TMZ. TMZ-Se also triggered greater autophagic response, as compared with TMZ, and suppressing autophagy partly rescued cell death induced by TMZ-Se, indicating that TMZ-Se-triggered autophagy contributed to cell death. Although mRNA level of the key autophagy gene, Beclin 1, was increased, Beclin 1 protein was down-regulated in the cells treated with TMZ-Se. The decrease in Beclin 1 following TMZ-Se treatment were rescued by the calpain inhibitors and the calpain-mediated degradation of Beclin1 had no effect on autophagy but promoted apoptosis in cells treated with TMZ-Se. CONCLUSIONS: Our study indicates that incorporation of Se into TMZ can render greater potency to this chemotherapeutic drug.

MK-2206, a novel allosteric inhibitor of Akt, synergizes with gefitinib against malignant glioma via modulating both autophagy and apoptosis.

Gefitinib, a small molecule inhibitor of the epidermal growth factor receptor tyrosine kinase, has been shown to induce autophagy as well as apoptosis in tumor cells. Yet, how to use autophagy and apoptosis to improve therapeutic efficacy of this drug against cancer remains to be explored. We reported here that MK-2206, a potent allosteric Akt inhibitor currently in phase I trials in patients with solid tumors, could reinforce the cytocidal effect of gefitinib against glioma. We found that cotreatment with gefitinib and MK-2206 increased the cytotoxicity of this growth factor receptor inhibitor in the glioma cells, and the CompuSyn synergism/antagonism analysis showed that MK-2206 acted synergistically with gefitinib. The benefit of the combinatorial treatment was also shown in an intracranial glioma mouse model. In the presence of MK-2206, there was a significant increase in apoptosis in glioma cells treated with gefitinib. MK-2206 also augmented the autophagy-inducing effect of gefitinib, as evidenced by increased levels of the autophagy marker, LC3-II. Inhibition of autophagy by silencing of the key autophagy gene, beclin 1 or 3-MA, further increased the cytotoxicity of this combinatorial treatment, suggesting that autophagy induced by these agents plays a cytoprotective role. Notably, at 48 hours following the combinatorial treatment, the level of LC3-II began to decrease but Bim was significantly elevated, suggesting a switch from autophagy to apoptosis. On the basis of the synergistic effect of MK-2206 on gefitinib observed in this study, the combination of these two drugs may be utilized as a new therapeutic regimen for malignant glioma.

Differential gene expression in tamoxifen-resistant breast cancer cells revealed by a new analytical model of RNA-Seq data.

Resistance to tamoxifen (Tam), a widely used antagonist of the estrogen receptor (ER), is a common obstacle to successful breast cancer treatment. While adjuvant therapy with Tam has been shown to significantly decrease the rate of disease recurrence and mortality, recurrent disease occurs in one third of patients treated with Tam within 5 years of therapy. A better understanding of gene expression alterations associated with Tam resistance will facilitate circumventing this problem. Using a next generation sequencing approach and a new bioinformatics model, we compared the transcriptomes of Tam-sensitive and Tam-resistant breast cancer cells for identification of genes involved in the development of Tam resistance. We identified differential expression of 1215 mRNA and 513 small RNA transcripts clustered into ERα functions, cell cycle regulation, transcription/translation, and mitochondrial dysfunction. The extent of alterations found at multiple levels of gene regulation highlights the ability of the Tam-resistant cells to modulate global gene expression. Alterations of small nucleolar RNA, oxidative phosphorylation, and proliferation processes in Tam-resistant cells present areas for diagnostic and therapeutic tool development for combating resistance to this anti-estrogen agent.

Dysfunction of nucleus accumbens-1 activates cellular senescence and inhibits tumor cell proliferation and oncogenesis.

Nucleus accumbens-1 (NAC1), a nuclear factor belonging to the BTB/POZ gene family, has emerging roles in cancer. We report here that NAC1 acts as a negative regulator of cellular senescence in transformed and nontransformed cells, and dysfunction of NAC1 induces senescence and inhibits its oncogenic potential. We show that NAC1 deficiency markedly activates senescence and inhibits proliferation in tumor cells treated with sublethal doses of γ-irradiation. In mouse embryonic fibroblasts from NAC1 knockout mice, following infection with a Ras virus, NAC1-/- cells undergo significantly more senescence and are either nontransformed or less transformed in vitro and less tumorigenic in vivo when compared with NAC1+/+ cells. Furthermore, we show that the NAC1-caused senescence blunting is mediated by ΔNp63, which exerts its effect on senescence through p21, and that NAC1 activates transcription of ΔNp63 under stressful conditions. Our results not only reveal a previously unrecognized function of NAC1, the molecular pathway involved and its impact on pathogenesis of tumor initiation and development, but also identify a novel senescence regulator that may be exploited as a potential target for cancer prevention and treatment.