PRMT1 Regulates EGFR and Wnt Signaling Pathways and Is a Promising Target for Combinatorial Treatment of Breast Cancer.

Identifying new therapeutic strategies for triple-negative breast cancer (TNBC) patients is a priority as these patients are highly prone to relapse after chemotherapy. Here, we found that protein arginine methyltransferase 1 (PRMT1) is highly expressed in all breast cancer subtypes. PRMT1 depletion decreases cell survival by inducing DNA damage and apoptosis in various breast cancer cell lines. Transcriptomic analysis and chromatin immunoprecipitation revealed that PRMT1 regulates the epidermal growth factor receptor (EGFR) and the Wnt signaling pathways, reported to be activated in TNBC. PRMT1 enzymatic activity is also required to stimulate the canonical Wnt pathway. Type I PRMT inhibitors decrease breast cancer cell proliferation and show anti-tumor activity in a TNBC xenograft model. These inhibitors display synergistic interactions with some chemotherapies used to treat TNBC patients as well as erlotinib, an EGFR inhibitor. Therefore, targeting PRMT1 in combination with these chemotherapies may improve existing treatments for TNBC patients.

Upgrade Rate of Atypical Ductal Hyperplasia: Ten Years Experience and Predictive Factors.

BACKGROUND: Atypical ductal hyperplasia (ADH) is a benign epithelial proliferative lesion with histologic features resembling those seen in low grade ductal carcinoma in situ (DCIS). Surgical excision of the biopsy site is the standard management approach. The objective of this study was to determine the upgrade rate from ADH on stereotactic breast biopsies to DCIS or invasive carcinoma (IC) in our institution. We also sought to identify clinical, pathologic and radiologic predictive factors associated with risk of upgrade. MATERIALS AND METHODS: Clinical charts, mammograms and pathology reports were reviewed for all women with a stereotactic breast biopsy showing ADH and subsequent surgery at our institution between 2008 and 2018. When available, mammograms were re-reviewed by a radiologist for this study. RESULTS: 295 biopsies were analyzed in 290 patients. Mean age was 56 y old. Upgrade rate was 10.5% of which 7.5% were DCIS and 3.1% IC. Mammograms were reviewed by a radiologist in 161 patients from 2013 to 2018. In this subset of patients, the rate of upgrade was 8.7% (4.35% DCIS and 4.35% IC). A statistically significant difference he largest size of the microcalcification clusters on mammogram was observed between the upgraded and the non-upgraded subgroups (14.2 mm versus 8.9 mm, P = 0.03) CONCLUSIONS: The evaluation of the largest size of microcalcification clusters on mammogram as a cut-off feature could be considered to choose between an observational versus a surgical approach. This large series provides contemporary data to assist informed decision making regarding the treatment of our patients.

Impact of Fasting Status on the Use of Klotho as a Biomarker.

BACKGROUND: Klotho is a protein secreted physiologically in humans. It acts like a hormone that regulates many biological processes. It is also a novel serological biomarker that is increasingly used as a predictive factor for several physiological and psychological conditions. Surprisingly, there is no consensus about the fasting state of the patient who is tested for klotho. Most studies are done on fasting patients, although others are done without concern about fasting status. There is a lack of evidence about this variable in klotho serological testing. Performing fasting tests on patients can be deleterious and can affect compliance. We investigated the effect of fasting status on klotho serological value. METHODS: We conducted an observational study in which klotho serology was evaluated in a fasting state and 2 h after a meal. In total, 35 participants came to the laboratory without having eaten for 10 h. Blood samples were taken on arrival at our laboratory and 2 h after eating a standardized meal. RESULTS: The mean age of our participants was 32.7 years old. There were 13 men and 22 women. In the fasting state, the klotho value was 1060.5 pg/mL (SD: 557.5 pg/mL). At 2 h after the meal, the klotho value was 1077.5 pg/mL (SD: 576.9 pg/mL). Statistical tests showed no difference before and after a meal in our study (P = 0.2425). CONCLUSIONS: Our results suggest that it is not necessary to perform klotho serology in a fasting state.

TIPIN depletion leads to apoptosis in breast cancer cells.

Triple-negative breast cancer (TNBC) is the breast cancer subgroup with the most aggressive clinical behavior. Alternatives to conventional chemotherapy are required to improve the survival of TNBC patients. Gene-expression analyses for different breast cancer subtypes revealed significant overexpression of the Timeless-interacting protein (TIPIN), which is involved in the stability of DNA replication forks, in the highly proliferative associated TNBC samples. Immunohistochemistry analysis showed higher expression of TIPIN in the most proliferative and aggressive breast cancer subtypes including TNBC, and no TIPIN expression in healthy breast tissues. The depletion of TIPIN by RNA interference impairs the proliferation of both human breast cancer and non-tumorigenic cell lines. However, this effect may be specifically associated with apoptosis in breast cancer cells. TIPIN silencing results in higher levels of single-stranded DNA (ssDNA), indicative of replicative stress (RS), in TNBC compared to non-tumorigenic cells. Upon TIPIN depletion, the speed of DNA replication fork was significantly decreased in all BC cells. However, TIPIN-depleted TNBC cells are unable to fire additional replication origins in response to RS and therefore undergo apoptosis. TIPIN knockdown in TNBC cells decreases tumorigenicity in vitro and delays tumor growth in vivo. Our findings suggest that TIPIN is important for the maintenance of DNA replication and represents a potential treatment target for the worst prognosis associated breast cancers, such as TNBC.

The histone chaperone HJURP is a new independent prognostic marker for luminal A breast carcinoma.

BACKGROUND: Breast cancer is a heterogeneous disease with different molecular subtypes that have varying responses to therapy. An ongoing challenge in breast cancer research is to distinguish high-risk patients from good prognosis patients. This is particularly difficult in the low-grade, ER-positive luminal A tumors, where robust diagnostic tools to aid clinical treatment decisions are lacking. Recent data implicating chromatin regulators in cancer initiation and progression offers a promising avenue to develop new tools to help guide clinical decisions. METHODS: Here we exploit a published transcriptome dataset and an independent validation cohort to correlate the mRNA expression of selected chromatin regulators with respect to the four intrinsic breast cancer molecular subtypes. We then perform univariate and multivariate analyses to compare the prognostic value of a panel of chromatin regulators to Ki67, a currently utilized proliferation marker. RESULTS: Unsupervised hierarchical clustering revealed a gene cluster containing several histone chaperones and histone variants highly-expressed in the proliferative subtypes (basal-like, HER2-positive, luminal B) but not in the luminal A subtype. Several chromatin regulators, including the histone chaperones CAF-1 (subunits p150 and p60), ASF1b, and HJURP, and the centromeric histone variant CENP-A, associated with local and metastatic relapse and poor patient outcome. Importantly, we find that HJURP can discriminate favorable and unfavorable outcome within the luminal A subtype, outperforming the currently utilized proliferation marker Ki67, as an independent prognostic marker for luminal A patients. CONCLUSIONS: The integration of chromatin regulators as clinical biomarkers, in particular the histone chaperone HJURP, will help guide patient substratification and treatment options for low-risk luminal A breast carcinoma patients.