Metastatic Adrenocortical Carcinoma: a Single Institutional Experience Abstract Adrenocortical carcinoma (ACC) is a rare malignancy with limited data to guide the management of metastatic disease. The optimal treatment strategies and outcomes of patients with metastatic ACC remain areas of active interest. We retrospectively reviewed patients with ACC who were treated with systemic therapy between January 1997 and October 2016 at The Ohio State University Comprehensive Cancer Center. Kaplan-Meier and Cox proportional hazards regression models were used for survival analysis. We identified 65 patients diagnosed with ACC during the given time period, and 36 patients received systemic therapy for distant metastatic disease. Median age at diagnosis was 50 (range 28–87). Median overall survival (OS) from time of diagnosis of ACC was 27 months (95% CI 19.6–39.3), and median OS from time of systemic treatment for metastatic disease was 18.7 months (95% CI 9.3–26.0). Clinical characteristics at time of initiation of systemic therapy were assessed, and presence of bone metastases (p = 0.66), ascites (p = 0.19), lung metastases (p = 0.12), liver metastases (p = 0.47), as well as hormonal activity of tumor (p = 0.19), were not prognostic for survival. Six patients with liver metastases treated with systemic therapy who received liver-directed therapy with either transarterial chemoembolization (TACE) or selective internal radiation therapy (SIRT) had longer survival than those who did not (p = 0.011). Our data expands the knowledge of clinical characteristics and outcomes of patients with ACC and suggests a possible role for incorporating liver-directed therapies for patients with hepatic metastases.

Assessing the Effect of Vitamin D Replacement on Basal Cell Carcinoma Occurrence and Recurrence Rates in Patients with Vitamin D Deficiency Abstract The study aimed to determine whether 25-OH vitamin D3 deficiency is present in patients with diagnosed BCC, and the effect of vitamin D replacement on the rates of BCC recurrence in patients with 25-OH vitamin D3 deficiency. In this prospective study, between 2012 and 2017, in the first stage, 25-OH vitamin D3 levels of all patients diagnosed with BCC between 2012 and 2013 were evaluated. In the second stage between 2014 and 2015, we evaluated the 25-OH vitamin D3 level of patients who had 25-OH vitamin D3 level < 25 ng/mL. All the patients included in the second stage had BCC recurrence. In the third stage, the patients who were diagnosed 25-OH vitamin D3 deficiency with BCC, between 2015 and 2017, were studied. The mean 25-OH vitamin D3 level of the patients in the second stage was 10.12 ng/mL. Recurrence was observed in 9.64% of the patients in the second stage. The mean level of serum 25-OH vitamin D3 in the third stage was 40.1 ng/mL, and 3.49% of these patients presented with recurrence. In all the patients as the initial diagnosis and following the 25-OH vitamin D3 level in all the patients with BCC recurrence, maintaining 25-OH vitamin D3 levels above 25 ng/mL can significantly reduce the recurrence rate.

Collagen and PAPP-A in the Etiology of Postpartum Breast Cancer Abstract Pregnancy has a dual effect on the risk of breast cancer. On one hand, pregnancy at a young age is known to be protective. However, pregnancy is also associated with a transient increased risk of breast cancer. For women that have children after the age of 30, the risk remains higher than women who never had children for decades. Involution of the breast has been identified as a window of mammary development associated with the adverse effect of pregnancy. In this review, we summarize the current understanding of the role of involution and describe the role of collagen in this setting. We also discuss the role of a collagen-dependent protease, pappalysin-1, in postpartum breast cancer and its role in activating both insulin-like growth factor signaling and discoidin domain collagen receptor 2, DDR2. Together, these novel advances in our understanding of postpartum breast cancer open the way to targeted therapies against this aggressive breast cancer sub-type.

Downregulation of miR-196-5p Induced by Hypoxia Drives Tumorigenesis and Metastasis in Hepatocellular Carcinoma Abstract In hepatocellular carcinoma (HCC), the hypoxic tumor microenvironment can drive enhance tumor malignancy and recurrence. The microRNA (miRNA) miR-196-5p has been shown to modulate the progression of several cancer types, but its roles in HCC remain uncertain. In the present report we observed significant miR-196-5p downregulation in HCC tissues and cells, and we found that the expression of this miRNA significantly impaired the proliferation and metastatic potential of HCC in vitro and in vivo. We identified high-mobility group AT-hook 2 (HMGA2) as a miR-196-5p target gene that was associated with the ability of miR-196-5p to modulate the progression of HCC. Expression of miR-196-5p and HMGA2 were correlated with the clinical characteristics and poor outcomes in patients with HCC. Finally, we found that hypoxic conditions were linked with reduced miR-196-5p expression in the context of HCC. Together these results highlight the role for miR-196-5p as an inhibitor of the proliferation and metastasis of HCC via the targeting of HMGA2, with this novel hypoxia/miR-196-5p/HMGA2 pathway serving as a potential target for future therapeutic intervention.

MiR-4500 Regulates PLXNC1 and Inhibits Papillary Thyroid Cancer Progression Abstract Although most patients with papillary thyroid cancer (PTC) are curable, there are still a few patients showing poor outcomes and increased risk of secondary cancers after therapies. In this study, we aimed to investigate the correlation between miR-4500 and PTC and to explore its molecular functions. A total of 50 patients were included, and sonography and histological examinations were used for diagnosis. Quantitative real-time polymerase chain reaction (qRT-PCR) was applied for detection of mRNA levels while Western blotting was used for measuring protein expression. Cell proliferation was tested using CCK-8 and colony formation assays. Caspase-3 activity and nucleosomal fragmentation assays were employed to test cell apoptosis. Cell invasive ability was measured using transwell assay. MiR-4500 target was identified using luciferase assay and RNA pull-down assay. MiR-4500 expression was significantly decreased in five PTC cell lines compared with Nthy-ori 3-1 cells and in PTC tissues compared with adjacent normal thyroid tissues, respectively. Decreased expression of miR-4500 showed lower survival rate, higher cancer stage, and lymphatic metastasis. Therefore, our results implied that miR-4500 could serve as a potential biomarker for PTC prognosis. Overexpression of miR-4500 repressed colony formation, proliferation, and invasiveness of PTC cells whereas increased cell apoptosis. We identified that PLXNC1 was a direct target of miR-4500. PLXNC1 knockdown showed similar effects on cell viability, colony formation, and cell apoptosis as overexpression of miR-4500 in PTC cells. In conclusion, miR-4500 inhibits the malignant transformation of PTC cells by directly targeting and repressing PLXNC1.

Association of Long-Term Dynamics in Circulating Testosterone with Serum PSA in Prostate Cancer-Free Men with Initial-PSA < 4 ng/mL Abstract We previously reported that an accelerated decline in circulating testosterone level is associated with a higher risk of prostate cancer (PCa). This study is to examine whether testosterone change rate is related to serum prostate-specific antigen (PSA) concentration among PCa-free men. Longitudinal data were derived from electronic medical records at a tertiary hospital in the Southeastern USA. PCa-free men with initial-PSA < 4 ng/mL and ≥ 2 testosterone measurements were included (n = 632). Three PSA measures (peak, the most recent, and average PSA) during the study period (from first testosterone measurement to the most recent hospital visit) were examined using multivariable-adjusted geometric means and were compared across quintiles of testosterone change rate (ng/dL/month) and current testosterone level (cross-sectional). Mean (standard deviation, SD) age at baseline was 59.3 (10.5) years; mean study period was 93.0 (55.3) months. After adjusting for covariates including baseline testosterone, the three PSA measures all significantly increased across quintile of testosterone change rate from increase to decline (peak PSA: quint 1 = 1.09, quint 5 = 1.41; the most recent PSA: quint 1 = 0.85, quint 5 = 1.00; average PSA: quint 1 = 0.89, quint 5 = 1.02; all Ptrend < 0.001). But current testosterone level was not associated with PSA levels. Stratified analyses indicated men with higher adiposity (body mass index > 24.1 kg/m2) or lower baseline testosterone (≤ 296 ng/dL) were more sensitive to testosterone change in regard to PSA. Among PCa-free men, accelerated testosterone decline might correlate with higher serum PSA concentration. It will help to elucidate the mechanisms relating aging-accompanying testosterone dynamics to prostate carcinogenesis.

Nuclear ErbB-2: a Novel Therapeutic Target in ErbB-2-Positive Breast Cancer? Abstract Membrane overexpression of ErbB-2 (MErbB-2), a member of the ErbB family of receptor tyrosine kinases, occurs in 15–20% of breast cancers (BC) and constitutes a therapeutic target in this BC subtype (ErbB-2-positive). Although MErbB-2-targeted therapies have significantly improved patients’ clinical outcome, resistance to available drugs is still a major issue in the clinic. Lack of accurate biomarkers for predicting responses to anti-ErbB-2 drugs at the time of diagnosis is also an important unresolved issue. Hence, a better understanding of the ErbB-2 signaling pathway constitutes a critical task in the battle against BC. In its canonical mechanism of action, MErbB-2 activates downstream signaling pathways, which transduce its proliferative effects in BC. The dogma of ErbB-2 mechanism of action has been challenged by the demonstration that MErbB-2 migrates to the nucleus, where it acts as a transcriptional regulator. Accumulating findings demonstrate that nuclear ErbB-2 (NErbB-2) is involved in BC growth and metastasis. Emerging evidence also reveal a role of NErbB-2 in the response to available anti-MErbB-2 agents. Here, we will review NErbB-2 function in BC and will particularly discuss the role of NErbB-2 as a novel target for therapy in ErbB-2-positive BC.

Recent Use of Oral Contraceptives and Risk of Luminal B, Triple-Negative, and HER2-Overexpressing Breast Cancer Abstract Oral contraceptive use is a well-established risk factor for breast cancer and is common among reproductive-aged women in the USA. Its relationship with less common, more aggressive, molecular subtypes is less clear. A population-based case-case analysis was conducted comparing three less common molecular subtypes to luminal A breast cancer among 1701 premenopausal cases aged 21–49 diagnosed with a first primary invasive breast cancer between 2004 and 2015. Medical record reviews and structured interviewer-administered questionnaires were used to collect data on oral contraceptive use. Multinomial logistic regression was used to estimate odds ratios (OR) and corresponding 95% confidence intervals (95% CI) for recency of oral contraceptive use for each subtype of breast cancer. Current use of oral contraceptives and use within 5 years before diagnosis was associated with lower odds of H2E tumors compared with luminal A tumors [OR = 0.5, 95% CI: 0.3, 0.9 and OR = 0.5, 95% CI: 0.4, 0.8, respectively] with increasing duration associated with decreasing odds (p for trend < 0.05). Oral contraceptive use was not associated with risks of TN or luminal B breast cancer. Oral contraceptive use may be more strongly positively associated with risks of luminal A, luminal B, and TN breast cancer than with risk of H2E tumors. These findings contribute to the etiological understanding of different molecular subtypes of breast cancer.

Estrogen Signaling in Endometrial Cancer: a Key Oncogenic Pathway with Several Open Questions Abstract Endometrial cancer is the most common gynecological cancer in the developed world, and it is one of the few cancer types that is becoming more prevalent and leading to more deaths in the USA each year. The majority of endometrial tumors are considered to be hormonally driven, where estrogen signaling through estrogen receptor α (ER) acts as an oncogenic signal. The major risk factors and some treatment options for endometrial cancer patients emphasize a key role for estrogen signaling in the disease. Despite the strong connections between estrogen signaling and endometrial cancer, important molecular aspects of ER function remain poorly understood; however, progress is being made in our understanding of estrogen signaling in endometrial cancer. Here, we discuss the evidence for the importance of estrogen signaling in endometrial cancer, details of the endometrial cancer-specific actions of ER, and open questions surrounding estrogen signaling in endometrial cancer.

Involvement of Aryl Hydrocarbon Receptor in l -Kynurenine-Mediated Parathyroid Hormone–Related Peptide Expression Abstract Parathyroid hormone-related peptide (PTHrP), produced by specific cancers such as lung cancer, profoundly influences the formation of bone metastatic lesions via the “vicious cycle” of tumor growth and bone resorption. The changes in gene expression regulated by the abnormal microenvironment components play key roles in maintaining the biological characteristics of cells, such as the organotropism of cancer metastasis. A recent study has shown that l-kynurenine (l-Kyn), one of microenvironment components, induced a substantial increase in the metastasis of lung cancer cells. What remains unclear, however, is the linkage between l-Kyn and bone metastatic lesions. In the present paper, we found that a significant upregulation of PTHrP expression was detected when 95D cells, a lung cancer cell line, were incubated with 50 μM of l-Kyn. Meanwhile, l-Kyn (50/100 μM) strongly strengthened aryl hydrocarbon receptor (Ahr) expression. Additionally, l-Kyn (50 μM) increased the expression of the nuclear translocation of Ahr and cytochrome P450 1A1. Most importantly, the l-Kyn-induced upregulation of migration was significantly reduced when cells were co-incubated with siRNAAhr. Notably, the l-Kyn-mediated increase in PTHrP was also substantially attenuated upon siRNAAhr treatment in 95D cells. These results suggest that Ahr is involved in the l-Kyn-induced enhancement of PTHrP expression.