A forward genetic screen identifies Sirtuin1 as a driver of neuroendocrine prostate cancer.

Although localized prostate cancer is relatively indolent, advanced prostate cancer manifests with aggressive and often lethal variants, including neuroendocrine prostate cancer (NEPC). To identify drivers of aggressive prostate cancer, we leveraged Sleeping Beauty (SB) transposon mutagenesis in a mouse model based on prostate-specific loss-of-function of Pten and Tp53 . Compared with control mice, SB mice developed more aggressive prostate tumors, with increased incidence of metastasis. Notably, a significant percentage of the SB prostate tumors display NEPC phenotypes, and the transcriptomic features of these SB mouse tumors recapitulated those of human NEPC. We identified common SB transposon insertion sites (CIS) and prioritized associated CIS-genes differentially expressed in NEPC versus non-NEPC SB tumors. Integrated analysis of CIS-genes encoding for proteins representing upstream, post-translational modulators of master regulators controlling the transcriptional state of SB -mouse and human NEPC tumors identified sirtuin 1 ( Sirt1 ) as a candidate mechanistic determinant of NEPC. Gain-of-function studies in human prostate cancer cell lines confirmed that SIRT1 promotes NEPC, while its loss-of-function or pharmacological inhibition abrogates NEPC. This integrative analysis is generalizable and can be used to identify novel cancer drivers for other malignancies. Summary: Using an unbiased forward mutagenesis screen in an autochthonous mouse model, we have investigated mechanistic determinants of aggressive prostate cancer. SIRT1 emerged as a key regulator of neuroendocrine prostate cancer differentiation and a potential target for therapeutic intervention.

Metformin Overcomes the Consequences of NKX3.1 Loss to Suppress Prostate Cancer Progression.

BACKGROUND: The antidiabetic drug metformin has known anticancer effects related to its antioxidant activity; however, its clinical benefit for prostate cancer (PCa) has thus far been inconclusive. Here, we investigate whether the efficacy of metformin in PCa is related to the expression status of NKX3.1, a prostate-specific homeobox gene that functions in mitochondria to protect the prostate from aberrant oxidative stress. OBJECTIVE: To investigate the relationship of NKX3.1 expression and metformin efficacy in PCa. DESIGN, SETTING, AND PARTICIPANTS: Functional studies were performed in vivo and in vitro in genetically engineered mouse models and human LNCaP cells, and organotypic cultures having normal or reduced/absent levels of NKX3.1. Correlative studies were performed using two independent retrospective tissue microarray cohorts of radical prostatectomies and a retrospective cohort of prostate biopsies from patients on active surveillance. INTERVENTION: Metformin was administered before or after the induction of oxidative stress by treatment with paraquat. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Functional endpoints included analyses of histopathology, tumorigenicity, and mitochondrial function. Correlative endpoints include Kaplan-Meier curves and Cox proportional hazard regression models. RESULTS AND LIMITATIONS: Metformin reversed the adverse consequences of NKX3.1 deficiency following oxidative stress in vivo and in vitro, as evident by reduced tumorigenicity and restored mitochondrial function. Patients with low NKX3.1 expression showed a significant clinical benefit from taking metformin. CONCLUSIONS: Metformin can overcome the adverse consequences of NKX3.1 loss for PCa progression by protecting against oxidative stress and promoting normal mitochondrial function. These functional activities and clinical correlates were observed only with low NKX3.1 expression. Thus, the clinical benefit of metformin in PCa may depend on the status of NKX3.1 expression. PATIENT SUMMARY: Prostate cancer patients with low NKX3.1 are likely to benefit most from metformin treatment to delay disease progression in a precision interception paradigm.

Clinicopathologic Profile and Psychosocial Experiences of Nigerian Breast Cancer Survivors.

PURPOSE: Breast cancer survivors are a distinct category of patients with unique characteristics and needs. The population of survivors is expected to increase, given the rising incidence of breast cancer in Nigeria, and the improvements in breast cancer outcomes. This study evaluated the clinicopathologic characteristics and the psychosocial experiences of a cohort of Nigerian breast cancer survivors. METHODS: From an institutional breast cancer database, patients managed between January 2010 and December 2016 were evaluated. Clinicopathologic characteristics, treatment details, and survival estimates were assessed. These were compared with nonsurvivors managed during the same period. Survivors were defined as those who have been alive for at least 5 years from the date of presentation. Qualitatively, a purposive sample of 20 survivors was evaluated using one-on-one in-depth interviews to assess their experiences and coping mechanisms after treatment. RESULTS: Of the 355 patients in the database during the study period, there were 163 survivors (45.9%), while 192 (54.1%) died. Age, stage at presentation, tumor size, and receipt of multiple treatment modalities were significantly associated with survival. Five themes were identified in qualitative analysis: initial reaction to the diagnosis, experiences during treatment, social support, coping strategies, and advocacy. Strong family support and spirituality were prominent coping strategies identified in this cohort. CONCLUSION: Despite obvious infrastructural and manpower limitations, Nigerian patients who present early and receive multimodal therapy and different breast cancer treatments have better odds of survival. Survivors have some unmet psychosocial and physical needs requiring intervention.

Prevalence and determinants of lymphedema in newly diagnosed Nigerian breast cancer patients using bioimpedance estimations.

Background: Breast cancer-related lymphedema (BCRL) is common and has significant impact on quality of life. Very little is known about BCRL in sub-Saharan Africa. Generally, BCRL has been mostly evaluated post treatment, with very limited data on the prevalence of pre-treatment BCRL at baseline. This study presents the prevalence and clinical associations of lymphedema among newly diagnosed, treatment-naive breast cancer patients in a Nigerian cohort using bioimpedance estimations. Methods: Consecutively consenting, newly diagnosed, treatment-naive breast cancer patients were assessed for upper limb lymphedema using bioimpedance measurements of the extracellular fluid and the single-frequency bioelectrical impedance analysis value at 5 kHz. Patients were classified as having lymphedema if there was >10% difference in arm measurements or if the ratios of the arm measurements were >3 SD above a normative mean generated from representative controls. Regression analysis was performed to determine clinical variables associated with lymphedema. Results: There were 154 breast cancer patients with a median age of 47 (40.0-56.8) years and a body mass index of 27 (23.5-30.9) kg/m2. The majority (70%) had stage III disease. All measurements were significantly higher in cases than controls. Using various definitions, the prevalence of lymphedema was between 11.7% and 14.3%. Various clinical variables relating to clinical stage were significantly associated with lymphedema. Conclusion: The predominance of locally advanced disease in the Nigerian setting is associated with high pre-treatment lymphedema rates. This may set the stage for higher rates in the post-operative setting. Management of lymphedema should be incorporated into the treatment planning.

Breast cancer in elderly patients: a clinicopathological review of a Nigerian database.

Background: Breast cancer in the elderly population has not been evaluated in the Nigerian context. With the rising incidence of breast cancer and the changing demographics, it is likely that an increasing number of elderly patients will be managed in the coming years in Nigeria. This review describes the clinicopathological profile of elderly patients with breast cancer in a Nigerian database. Method: From a prospective institutional database, elderly patients (65 years and above) managed for breast cancer over a 9-year period were reviewed. Details of their socio-demographic characteristics, patterns of presentation, pathology, treatment and outcome were obtained and analysed. Results: Of the 607 patients managed during the study period, there were 87 older patients accounting for 14.3% of the total. There was a progressive rise in the number of patients with breast cancer towards the latter part of the study. Expectedly, they were all post-menopausal, with their ages ranging from 65 to 92 years, with a mean of 71 ± 6.58 years. Systemic hypertension was the commonest co-morbidity (29.8%). The mean tumour size at presentation was 10 cm, with the majority presenting with stage 3 disease. Invasive ductal carcinoma was the predominant histological type 83 (95.4%); 44.4% of those who had immunohistochemistry were oestrogen receptor-positive. Approximately half underwent mastectomy (52.8%), 63 (72.4%) had chemotherapy, 8 (44.4%) had hormonal therapy and only 6 (6.9%) had combined multimodal therapy in addition to surgery. Overall 5-year survival was 42.1%. Conclusion: The pattern of presentation and outcomes of care in this elderly cohort is similar to the general population. Early presentation and use of multimodal treatment is still the mainstay of survival.

NKX3.1 Localization to Mitochondria Suppresses Prostate Cancer Initiation.

Mitochondria provide the first line of defense against the tumor-promoting effects of oxidative stress. Here we show that the prostate-specific homeoprotein NKX3.1 suppresses prostate cancer initiation by protecting mitochondria from oxidative stress. Integrating analyses of genetically engineered mouse models, human prostate cancer cells, and human prostate cancer organotypic cultures, we find that, in response to oxidative stress, NKX3.1 is imported to mitochondria via the chaperone protein HSPA9, where it regulates transcription of mitochondrial-encoded electron transport chain (ETC) genes, thereby restoring oxidative phosphorylation and preventing cancer initiation. Germline polymorphisms of NKX3.1 associated with increased cancer risk fail to protect from oxidative stress or suppress tumorigenicity. Low expression levels of NKX3.1 combined with low expression of mitochondrial ETC genes are associated with adverse clinical outcome, whereas high levels of mitochondrial NKX3.1 protein are associated with favorable outcome. This work reveals an extranuclear role for NKX3.1 in suppression of prostate cancer by protecting mitochondrial function. SIGNIFICANCE: Our findings uncover a nonnuclear function for NKX3.1 that is a key mechanism for suppression of prostate cancer. Analyses of the expression levels and subcellular localization of NKX3.1 in patients at risk of cancer progression may improve risk assessment in a precision prevention paradigm, particularly for men undergoing active surveillance.See related commentary by Finch and Baena, p. 2132.This article is highlighted in the In This Issue feature, p. 2113.