More than a duologue: In-depth insights into epitranscriptomics and ferroptosis.

Beyond transcription, RNA molecules are enzymatically modified to influence the biological functions of living organisms. The term "epitranscriptomics" describes the changes in RNA strands aside from altering the innate sequences. Modifications on adenosine (A) are the most widely characterized epitranscriptomic modification, including N6-methyladenosine (m6A), N1-methyladenosine (m1A), polyadenylation, and adenosine-to-inosine (A-to-I) RNA editing, and modifications on other nucleotides seem to be fewer, such as N7-methylguanosine (m7G), 5-methylcytosine (m5C), and pseudouridine (Ψ). These changes on the RNA strand surface, exclusively by their RNA-modifying proteins (RMPs), are reported in various biological phenomena, including programmed cell death (PCD). One necro-biological phenomenon that has been observed for long but has started to gain heed in recent years is "ferroptosis." The phospholipid peroxidation by polyunsaturated-fatty-acid-containing-phospholipid hydroperoxyl (PLOOH) radicals destroys membrane integrity due to a series of mechanisms. The Fenton reaction, constituting the final Haber-Weiss reaction that is less recognized, collaboratively leading to the conversion of polyunsaturated fatty acid (PUFA) to PLOOH, is the etymological origin of ferroptosis. However, it is with increasing evidence that ferroptotic signaling is also intervened by epitranscriptomic modifications, although the truth is still ambiguous. We attempted to delineate some up-to-date discoveries on both epitranscriptomics and ferroptosis, bringing up the fundamentals to address any potential connection between the two. Next, we discussed whether a duologal relationship, or more, exists between the two, taking the ROS level and iron status into consideration. Lastly, we surveyed future perspectives that would favor the understanding of these topics.

HOMER3 facilitates growth factor-mediated ß-Catenin tyrosine phosphorylation and activation to promote metastasis in triple negative breast cancer.

BACKGROUND: HOMER family scaffolding proteins (HOMER1-3) play critical roles in the development and progression of human disease by regulating the assembly of signal transduction complexes in response to extrinsic stimuli. However, the role of HOMER protein in breast cancer remains unclear. METHODS: HOMER3 expression was examined by immunohistochemistry in breast cancer patient specimens, and its significance in prognosis was assessed by Kaplan-Meier survival analysis. The effects of HOMER3 in growth factor-induced ß-Catenin activation were analyzed by assays such as TOP/FOP flash reporter, tyrosine phosphorylation assay and reciprocal immunoprecipitation (IP) assay. Role of HOMER3 in breast cancer metastasis was determined by cell function assays and mice tumor models. RESULTS: Herein, we find that, among the three HOMER proteins, HOMER3 is selectively overexpressed in the most aggressive triple negative breast cancer (TNBC) subtype, and significantly correlates with earlier tumor metastasis and shorter patient survival. Mechanismly, HOMER3 interacts with both c-Src and ß-Catenin, thus providing a scaffolding platform to facilitate c-Src-induced ß-Catenin tyrosine phosphorylation under growth factor stimulation. HOMER3 promotes ß-Catenin nuclear translocation and activation, and this axis is clinically relevant. HOMER3 promotes and is essential for EGF-induced aggressiveness and metastasis of TNBC cells both in vitro and in vivo. CONCLUSION: These findings identify a novel role of HOMER3 in the transduction of growth factor-mediated ß-Catenin activation and suggest that HOMER3 might be a targetable vulnerability of TNBC.

Epigenetic silencing of SALL2 confers tamoxifen resistance in breast cancer.

Resistance to tamoxifen is a clinically major challenge in breast cancer treatment. Although downregulation of estrogen receptor-alpha (ERα) is the dominant mechanism of tamoxifen resistance, the reason for ERα decrease during tamoxifen therapy remains elusive. Herein, we reported that Spalt-like transcription factor 2 (SALL2) expression was significantly reduced during tamoxifen therapy through transcription profiling analysis of 9 paired primary pre-tamoxifen-treated and relapsed tamoxifen-resistant breast cancer tissues. SALL2 transcriptionally upregulated ESR1 and PTEN through directly binding to the DNA promoters. By contrast, silencing SALL2 induced downregulation of ERα and PTEN and activated the Akt/mTOR signaling, resulting in estrogen-independent growth and tamoxifen resistance in ERα-positive breast cancer. Furthermore, hypermethylation of SALL2 promoter was found in tamoxifen-resistant breast cancer. Importantly, in vivo experiments showed that DNA methyltransferase inhibitor-mediated SALL2 restoration resensitized tamoxifen-resistant breast cancer to tamoxifen therapy. These findings shed light on the mechanism of SALL2 in regulation of ER and represent a potential clinical signature that can be used to categorize breast cancer patients who may benefit from co-therapy with tamoxifen and DNMT inhibitor.

Could local surgery improve survival in de novo stage IV breast cancer?

BACKGROUND: Resection of the primary tumor is recommended for symptom relief in de novo stage IV breast cancer. We explored whether local surgery could provide a survival benefit in these patients and attempted to characterize the population that could benefit from surgery. METHODS: Metastatic Breast cancer patients (N = 313) with intact primary tumor between January 2006 and April 2013 were separated into two groups according to whether or not they had undergone surgery. The difference in characteristics between the two groups was analyzed using chi-square test, Fisher's exact test and Mann-Whitney test. Univariable and multivariable Cox regression and stratified survival analysis were used to assess the effect of surgery on survival. RESULTS: Of the 313 patients, 188 (60.1%) underwent local surgery. Patients with local surgery had a 47% reduction in mortality risk vs. those with no surgery (median survival 78 months vs. 37 months; HR = 0.53; 95% CI, 0.36-0.78) after adjustment for clinical and tumor characteristics. Stratified survival analysis showed that patients with bone metastasis alone (and primary tumor ≤5 cm), soft tissue metastasis, or ≤ 3 metastasis sites benefit from surgery. CONCLUSION: Surgical resection of the primary tumor can improve survival in selected de novo stage IV breast cancer patients.

Patterns of Occurrence and Outcomes of Contralateral Breast Cancer: Analysis of SEER Data.

Population-based estimates are lacking for the temporal trends in the contralateral breast cancer (CBC) risk for patients with breast cancer (BC). Data for BC patients diagnosed with CBC were collected from the Surveillance, Epidemiology, and End Results database. CBC incidence was calculated using the Kaplan-Meier method and the temporal trend in CBC incidence was assessed using joinpoint regression. Survival analysis was calculated using propensity scoring (PS) and multivariate Cox regression with a competing risk model. We found that 10,944 of 212,630 patients with early-stage BC were subsequently diagnosed with secondary BC in the contralateral breast. The 5-, 10-, 15-, and 20-year cumulative CBC incidences were 1.9, 4.6, 7.6, and 10.5%, respectively. Being younger (.

ANP32E induces tumorigenesis of triple-negative breast cancer cells by upregulating E2F1.

Triple-negative breast cancer (TNBC) lacks expression of estrogen receptor (ER), progesterone receptor, and the HER2 receptor; it is highly proliferative and becomes the deadliest forms of breast cancer. Effective prognostic methods and therapeutic targets for TNBC are required to improve patient outcomes. Here, we report that acidic nuclear phosphoprotein 32 family member E (ANP32E), which promotes cell proliferation in mammalian development, is highly expressed in TNBC cells compared to other types of breast cancer. High expression of ANP32E correlates significantly with worse overall survival (OS; P < 0.001) and higher risks of disease recurrence (P < 0.001) in patients with TNBC. Univariate and multivariate Cox-regression models show that ANP32E is an independent prognostic factor in TNBC. Furthermore, we discovered that ANP32E promotes tumor proliferation in vitro by inducing G1/S transition, and ANP32E inhibition suppresses tumor formation in vivo. By examining the expression of E2F1, cyclin E1, and cyclin E2, we discovered that ANP32E promotes the G1/S transition by transcriptionally inducing E2F1. Taken together, our study shows that ANP32E is an efficient prognostic marker, and it promotes the G1/S transition and induces tumorigenesis of TNBC cells by transcriptionally inducing E2F1.

Bone metastasis pattern in initial metastatic breast cancer: a population-based study.

PURPOSE: Bone is one of the most common sites of breast cancer metastasis, and population-based studies of patients with bone metastasis in initial metastatic breast cancer (MBC) are lacking. MATERIALS AND METHODS: From 2010 to 2013, 245,707 breast cancer patients and 8901 patients diagnosed with initial bone metastasis were identified by Surveillance, Epidemiology, and End Results database of the National Cancer Institute. Multivariate logistic and Cox regression were used to identify predictive factors for the presence of bone metastasis and prognosis factors. Kaplan-Meier method and log-rank test were used for survival analysis. RESULTS: Eight thousand nine hundred one patients with initial MBC had bone involvement, accounting for 3.6% of the entire cohort and 62.5% of the patients with initial MBC. Also, 70.5% of patients with bone metastasis were hormone receptor (HR) positive (HR+/human epidermal growth factor receptor 2 [HER2]-: 57.6%; HR+/HER2+: 12.9%). Patients with initial bone metastasis had a better 5-year survival rate compared to those with initial brain, liver, or lung metastasis. HR+/HER2- and HR+/HER2+ breast cancer had a propensity of bone metastasis in the entire cohort and were correlated with better prognosis in patients with initial bone metastasis. Local surgery had significantly improved overall survival in initial MBC patients with bone metastasis. CONCLUSION: Our study has provided population-based estimates of epidemiologic characteristics and prognosis in patients with bone metastasis at the time of breast cancer diagnosis. These findings would lend support to optimal surveillance and treatment of bone metastasis in breast cancer.

Score for the Survival Probability in Metastasis Breast Cancer: A Nomogram-Based Risk Assessment Model.

PURPOSE: Survival of metastatic breast cancer (MBC) patient remains unknown and varies greatly from person to person. Thus, we aimed to construct a nomogram to quantify the survival probability of patients with MBC. MATERIALS AND METHODS: We had included 793 MBC patients and calculated trends of case fatality rate by Kaplan-Meier method and joinpoint regression. Six hundred thirty-four patients with MBC between January 2004 and July 2011 and 159 patients with MBC between August 2011 and July 2013 were assigned to training cohort and internal validation cohort, respectively. We constructed the nomogram based on the results of univariable and multivariable Cox regression analyses in the training cohort and validated the nomogram in the validation cohort. Concordance index and calibration curves were used to assess the effectiveness of nomogram. RESULTS: Case fatality rate of MBC was increasing (annual percentage change [APC], 21.6; 95% confidence interval [CI], 1.0 to 46.3; p < 0.05) in the first 18 months and then decreased (APC, ‒4.5; 95% CI, ‒8.2 to ‒0.7; p < 0.05). Metastasis-free interval, age, metastasis location, and hormone receptor status were independent prognostic factors and were included in the nomogram, which had a concordance index of 0.69 in the training cohort and 0.67 in the validation cohort. Calibration curves indicated good consistency between the two cohorts at 1 and 3 years. CONCLUSION: In conclusion, the fatality risk of MBC was increasing and reached the summit between 13th and 18th month afterthe detection of MBC. We have developed and validated a nomogram to predict the 1- and 3-year survival probability in MBC.