Hormones & Cancer最新文献

Primary hyperparathyroidism (pHPT) is associated with familial syndromes such as multiple endocrine neoplasia type 1 (MEN1), 2A (MEN2A), MEN-like syndromes (CDKN1B), and CDC73-related disorder (hyperparathyroidism - jaw tumor syndrome (HPJT)). Familial hypocalciuric hypercalcemia (FHH) caused by CASR variants is an important differential diagnosis for pHPT. In order to evaluate the contribution of hereditary causes to pHPT in patients encountered in a specialized clinic, we conducted a retrospective study on patients with pHPT that underwent germline genetic testing. We evaluated 46 patients referred to a Cancer Genetics Clinic. Reasons for referral were young age (age < 40) for 29 patients (63%), multi-gland disease for 23 patients (50%), and a positive family history of pHPT for 11 patients (24%). All 46 patients underwent genetic evaluation. A total of 11 rare variants were found (CASR (4), CDC73 (2), MEN1 (2) CDKN1B (1), and RET (2)). One MEN1 variant was classified as pathogenic, and all others were variants of uncertain significance (VUS). All patients with CASR variants had clinical features of FHH and were counselled against parathyroidectomy. Both patients with CDC73 variants were counselled about recurrence of pHPT and parathyroid cancer. Neither of the RET variants were MEN2-associated. The CDKN1B variant was regarded as a true VUS and no action was taken. In this study, genetic testing impacted clinical care in 7 (15%) patients. We suggest that all patients < 40 years of age, with multi-gland disease, single gland disease refractory to treatment, and a positive family history for pHPT or associated tumors should be considered for genetic evaluation.

The hormone receptor-positive (estrogen and/or progesterone receptor (PR)-positive) and HER2-negative breast cancer (BC) subtype is a biologically heterogeneous entity that includes luminal A-like (LumA-like) and luminal B-like (LumB-like) subtypes. Decreased PR levels is a distinctive biological feature of LumB-like tumors. These tumors also show reduced sensitivity to endocrine therapies and poorer prognosis than LumA-like tumors. Identification of biomarkers to accurately predict disease relapse in these subtypes is crucial in order to select effective therapies. We identified the tumor suppressor PDCD4 (programmed cell death 4), located in the nucleus (NPDCD4), as an independent prognostic factor of good clinical outcome in LumA-like and LumB-like subtypes. NPDCD4-positive LumB-like tumors presented overall and disease-free survival rates comparable to those of NPDCD4-positive LumA-like tumors, indicating that NPDCD4 improves the outcome of LumB-like patients. In contrast, NPDCD4 loss increased the risk of disease recurrence and death in LumB-like compared with LumA-like tumors. This, along with our results showing that LumB-like tumors present lower NPDCD4 positivity than LumA-like tumors, suggests that NPDCD4 loss contributes to endocrine therapy resistance in LumB-like BCs. We also revealed that PR induces PDCD4 transcription in LumB-like BC, providing a mechanistic explanation to the low PDCD4 levels in LumB-like BCs lacking PR. Finally, PDCD4 silencing enhanced BC cell survival in a patient-derived explant model of LumB-like disease. Our discoveries highlight NPDCD4 as a novel biomarker in LumA- and LumB-like subtypes, which could be included in the panel of immunohistochemical markers used in the clinic to accurately predict the prognosis of LumB-like tumors.

Breast cancer is a complex disease, and it is the most common cause of morbidity and mortality among women worldwide. In Sub-Saharan Africa, the clinical characteristics and tumor profiles of breast cancer are still unknown. In the present study we aimed to determine breast tumor profiles of the Rwandan patients in relation to age and tumor stages. We compare our findings to related results from other sub-Saharan Africa studies. Data on age at diagnosis, tumor stage, and hormonal profiles of 138 patients diagnosed between January 2015 and December 2018 were retrospectively retrieved from electronic medical records at three referral hospitals in Rwanda. We compared our results to related findings reported in other Sub-Saharan African countries. All statistical analyses were done using SPSS Inc., Chicago, IL, USA, version 20 and R software languages. The mean age at diagnosis was 49.7 years (SD = 13) and ranged from 17 to 86 years. The majority of patients (57.2%) were diagnosed before 50 years of age compared with 42.8% aged > 50 years. Tumor stage III was the commonest accounting for 62% followed by stage II with 24.8%. The distribution of breast tumor subtypes was ER-, PR-, HER2-: 37.7%; ER+, PR+, HER2-: 31.2%; ER-, PR-, HER2+: 14.5%; ER+, PR+, HER2+: 5.1%; and other subtypes represented 11.6%. There was no statistically significant difference in age and tumor stages between the molecular subtypes. Our findings revealed the predominance of hormonal negative tumors among Rwandan patients with breast cancer. Triple negative was found to be the most common breast tumor subtype regardless of age and tumor stage. Larger prospective studies could examine genetics and environmental factors that may play a role in the differences of tumor characteristics in Sub-Saharan populations.

Thyroid cancer is the most common endocrine malignancy and incidences are rising rapidly, in both pediatric and adult populations. Many thyroid tumors are successfully treated which results in low mortality rates, but there is often a significant morbidity associated with thyroid cancer treatments. For patients with tumors that are not successfully treated with surgical resection or radioactive iodine treatment, prognosis is dramatically reduced. Patients diagnosed with anaplastic thyroid cancer face a very grim prognosis with a median survival of 6 months post-diagnosis. There is a critical need to identify patients who are at greatest risk of developing persistent disease and progressing to poorly differentiated or anaplastic disease. Furthermore, development of treatments associated with less morbidity would represent a significant improvement for thyroid cancer survivors. It is well established the stromal cells and components of the tumor microenvironment can drive tumor progression and resistance to therapy. Here we review the current state of what is known regarding the thyroid tumor microenvironment and how these factors may contribute to thyroid tumor pathogenesis. Study of the tumor microenvironment within thyroid cancer is a relatively new field, and more studies are needed to dissect the complex and dynamic crosstalk between thyroid tumor cells and its tumor niche.

Prostate cancer (PCa) is the most common cancer and the second leading cause of cancer-related deaths of men in Western countries. Androgen deprivation therapy is initially successful, however eventually fails, and tumors progress to the more aggressive castration-resistant PCa (CRPC). Yet, androgen receptor (AR) usually remains as a major regulator of tumor cell proliferation in CRPC. Interleukin-23 (IL-23) was recently shown to promote the development of CRPC by driving AR transcription. Here we used the androgen-sensitive LNCaP, castration-resistant C4-2, and 22Rv1 cells. Interestingly, cellular senescence is induced in these human cell lines by treatment with the AR antagonists enzalutamide (ENZ) or darolutamide (ODM), which might be one underlying mechanism for inhibition of PCa cell proliferation. Treatment with IL-23 alone did not change cellular senescence levels in these cell lines, whereas IL-23 inhibited significantly cellular senescence levels induced by ENZ or ODM in both CRPC cell lines C4-2 and 22Rv1 but not in LNCaP cells. This indicates a response of IL-23 specific in CRPC cells. Generating LNCaP and C4-2 three-dimensional (3D) spheroids and treatment with AR antagonists resulted in the reduced spheroid volume and thus growth inhibition. However, the combination of AR antagonists with IL-23 did not affect the antagonist-mediated reduction of spheroid volumes. This observation was confirmed with proliferation assays using adherent monolayer cell cultures. Taken together, the data indicate that IL-23 treatment reduces the AR antagonists-induced level of cellular senescence of CRPC cells, which could be one possible mechanism for promoting castration resistance.

ER+/PR- (estrogen receptor positive and progesterone receptor negative) tumors constitute only a small portion of the breast cancer population. Patients with ER+/PR- tumors, however, are characterized by worse survival compared to patients with ER+/PR+ (estrogen receptor positive and progesterone receptor positive) tumors. Controversy exists regarding the efficacy of hormone blocking therapy for patients with ER+/PR- tumors. The NCDB was queried between 2004 and 2015, and patients with invasive ER+/PR- tumors were identified. We employed univariate Cox proportional hazards to compare outcomes among patients that did or did not receive hormone blocking therapy. We identified 138,398 patients with invasive ER+/PR- tumors, 32,044 (23%) of whom did not receive hormone blocking therapy. The reasons for not receiving hormone blocking therapy included contraindications to treatment, death, patient refusal, and unknown. There were no significant differences in race, income quartile, or education quartile between patients who did and did not receive hormone blocking therapy. Patients who did not receive hormone blocking therapy underwent surgical assessment of the axilla more frequently than those who did receive hormone therapy. Our analysis demonstrated that hormone blocking therapy administration was associated with increased overall survival for up to 10 years of follow up (HR: 0.58; 95% CI: 0.56-0.59, p < 0.001). Hormone blocking therapy may be associated with increased survival for breast cancer patients with ER+/PR- tumors. Although this benefit may last for years after completion of the course, up to 25% of patients do not receive this treatment. Strategies to increase the utilization and adherence to hormone blocking therapy regimens may improve patient survival outcomes.

Fine needle aspiration biopsy does not permit to distinguish between benign and malignant follicular thyroid lesions (category IV in the Bethesda Cytopathology System). Some reports have suggested an association between increased serum TSH levels and thyroid cancer, so the aim of this study was to investigate the association between TSH levels and malignancy in patients with follicular thyroid nodules. Therefore, we conducted a retrospective study of all subjects who underwent surgical treatment for Bethesda IV thyroid nodules in a single center (years 2012-2017). A total of 127 patients were analyzed, and malignancy was present in 38.6% of the patients. Using ROC analysis, the best TSH cut-off point to differentiate benign from malignant disease was 2.1 mU/l and the age cut-off with better sensitivity and specificity was 47 years. The proportion of subjects with TSH ≥ 2.1 mU/l was greater among subjects with cancer than in those with benign diseases (65.3 vs 44.9%, P = 0.029). The concurrence of both cut-off points (TSH ≥ 2.1 mU/l and age ≥ 47 years) showed a higher diagnostic accuracy than either of the two variables separately. Therefore, the present study supports an association between serum concentrations of TSH and risk of malignancy among subjects with Bethesda IV thyroid nodules. TSH levels could modify the diagnostic and therapeutic approach of patients with Bethesda IV nodules.

The development of breast cancer (BC) is influenced by age, overweight, obesity, metabolic syndrome, and diabetes mellitus (DM), which are associated with hyperglycemia, glucose intolerance, insulin resistance, and oxidative stress. High glucose concentration increases a metastatic phenotype in cultured breast cancer cells, promoting cell proliferation, reactive species production (ROS), epithelial mesenchymal transition (EMT), and expression of proteolytic enzymes. Our aim was to determine whether diabetes mellitus favor BC progression in mice and its association with changes in the content of ROS and glycolytic and proteolytic enzymes. Diabetes was induced in 7-week-old Balb/c mice, under 6-h fasting with a unique i. p. dose of streptozotocin 120 mg/kg. Furthermore, 4T1 breast cancer cells were injected beneath the nipple to induce tumors. G6PD, GAPDH, ENO1, uPA, uPAR, PAI-1, β-catenin, Snail, vimentin, and E-cadherin were measured by western blot and MPP-9 and MMP-2 by gel zymography. TBARS were measured as markers of the lipid peroxidation. Lower survival and increased tumor growth, together with marked EMT, were found in diabetic in comparison with nondiabetic mice. The effects of diabetes were associated with enhanced lipid peroxidation and higher levels of glycolytic (G6PD, GAPDH, and ENO1) and proteolytic (uPA, MMP-9) enzymes. Possibly, hyperglycemia and ROS led to faster progression of breast cancer in diabetic mice, fomenting EMT and the expression of glycolytic and proteolytic enzymes. These enzymes participate in the supply of energy and precursors for macromolecular biosynthesis and extracellular matrix degradation during breast cancer progression.

Previous studies reported heterogeneous associations between obesity and reproductive-related breast cancer risk factors and breast cancer intrinsic subtypes; however, few studies have been conducted in Asian populations. Here, we aimed to examine whether risks associated with established breast cancer risk factors varied by breast cancer subtypes in Chinese women. We conducted a hospital-based case-control study in Hong Kong, including a total of 2169 Chinese women. Unconditional polytomous logistic regression models were used to calculate adjusted odds ratios (AORs) and 95% confidence intervals(95%CIs) to estimate relative risks associated with examined risk factors in case-control analyses and to test for heterogeneity across breast cancer subtypes in case-case analyses. In case-case analyses, compared with luminal A patients, luminal B (AOR = 1.76, 95% CI = 1.07-2.88), HER2 overexpressing (AOR = 3.40, 95% CI = 1.56-7.39), and triple negative (TNBC, AOR = 2.39, 95% CI = 1.18-4.82) patients were more likely to be postmenopausal. In case-control analyses, reduced risks associated with parity and younger age at first birth were only seen for luminal A and B cases especially among postmenopausal women, whereas having ≥ 3 children was associated with increased risk for HER2 overexpressing and TNBC among premenopausal women. Obesity was associated with increased risk for all subtypes. We found heterogeneous associations between parity-related risk factors by menopausal status and breast cancer subtypes among Chinese patients, which is similar to those observed in Western populations. Interestingly, obesity was associated with increased breast cancer risk regardless of menopausal status or subtypes, except for premenopausal luminal patients, which appears to be unique in Asian populations.