- TFEB, SIRT1, CARM1, Beclin-1 expression and PITX2 methylation in breast cancer chemoresistance: a retrospective study. - Background: Breast cancer chemoresistance is attributed to a wide variety of mechanisms, including autophagy.. - Objective: This study aims to evaluate the prognostic impact of TFEB and its pathway in breast cancer chemoresistance.. - A group of breast cancer patients treated with chemotherapy, who relapsed within 12 months from treatment initiation, were compared to a sub-cohort of chemo-treated patients who did not recur within 12 months of follow-up. - In the final model, 136 cases of chemo-treated breast cancer were included.. - Results: A higher TFEB and Beclin-1 expression correlate with shorter survival in patients with chemo-treated invasive breast cancer (respectively HR 3.46, CI p <. - A high TFEB expression correlates with shorter sur- vival in patients with chemo-treated invasive breast cancer;. - A high Beclin-1 expression correlates with shorter survival in patients with chemo-treated invasive breast cancer;. - TFEB, SIRT1, and Beclin-1 seem to have a potential prognostic significance in patients with chemo-treated breast cancer.. - Breast cancer comprises mul- tiple subtypes that present different prognostic outcomes and various molecular patterns [3, 4]. - The breast cancer molecular subtypes include luminal A, luminal B, lu- minal HER2, HER2 enriched, and basal-like [5]. - As in other cancer histotypes, the role of autophagy and chemoresistance in breast cancer is a critical issue.. - changes in molecular signaling networks, and it was found to be a prognostic biomarker in breast cancer [23]. - In particular, the methylation of PITX2 has been found to predict sensitivity to anthracycline-based chemotherapy in breast cancer [24–27].. - This study’s main objective is to assess the prognostic role of TFEB, CARM1, SIRT1, and Beclin-1 in chemo- treated breast carcinoma and compare the TFEB, CARM1, SIRT1, and Beclin-1 expression with the methylation of PITX2 in breast cancer treated with chemotherapy.. - In this study, all breast cancer cases treated by adju- vant or neoadjuvant chemotherapy between January 2002 and December 2016 were included in order to have at least 12 months of follow-up. - Furthermore, all of the following cases were excluded from the study: those without a documented follow-up, breast cancer patients who did not undergo adjuvant or neoadjuvant treatments, and male patients.. - This retrospective observational study reviews patho- logical archives and medical records to identify breast cancer cases treated by adjuvant or neoadjuvant chemo- therapy. - It was composed of a ran- dom group of 163 of the 894 eligible women (hereafter called the subcohort) together with all eligible women diagnosed with a breast cancer recurrence within 12 months of treatment initiation. - The final sample included 203 women: 163 belonging to the subcohort and 42 breast cancer patients who ex- perienced recurrence within a 12-month follow-up. - In the case-control sample selection, all breast cancer patients included in the tissue micro-array were consid- ered. - We analyzed the presence and the quantity of mRNA and the relative protein synthesis in the selected breast cancer tumor samples. - Along with the RT-PCR analysis, TFEB, CARM1, and SIRT1 protein expressions for all breast cancer cases in our samples were investigated by immunohistochemis- try. - Therascreen® PITX2 RGQ PCR kit is a methylation-specific PCR (MSP) based on real-time PCR, intended for the quantitative assessment of percent methylation ratio (PMR) in the promoter 2 (P2) of the PITX2 gene and it was validated in primary formalin- fixed paraffin-embedded breast cancer tissue . - All primary formalin-fixed paraffin-embedded breast cancer tissue samples were coded to ensure blinding of the operator while conducting the PITX2 DNA methylation assay.. - The blocks for the creation of the TMA were then collected.. - Table 1 shows a description of the included samples.. - The median age at breast cancer surgery was 55 years (48–65), and the median BMI was 25 kg/m2 (IQR 22–. - A Image at 20x (and in the box at 40x) of primary breast cancer tissue TFEB immunohistochemical staining in a patient with breast cancer recurrence within 12 months of follow-up. - B Image at 20x (and in the box at 40x) of TFEB immunohistochemical staining in a patient ’ s primary breast cancer tissue without recurrence within 12 months of follow-up. - C 20x image (and in the 40x square) of CARM1 immunohistochemical staining in primary breast cancer tissue of a woman with recurrent breast cancer within 12 months of follow-up. - D 20x image (and in the 40x frame) of CARM1 immunohistochemical staining in a primary breast cancer specimen of a patient which did not recure within 12 months of follow-up. - E Image at 20x (and in the box at 40x) of SIRT1 immunohistochemical staining in a primary breast cancer specimen of a woman with recurrent breast cancer within 12 months of follow-up. - immunohistochemical staining in a primary breast cancer specimen of a woman without tumor recurrence within 12 months of follow-up. - G Image at 20x (and in the box at 40x) of Beclin-1 immunohistochemical staining in a primary breast cancer specimen of a woman with recurrent breast cancer within 12 months of follow-up. - H Image at 20x (and in the box at 40x) of Beclin-1 immunohistochemical staining in a primary breast cancer specimen of a woman without tumor recurrence within 12 months of follow-up. - of the distribution [>. - 100] or low, i.e., with an H-score lower than or equal to the first quartile of the distribution. - of the distribution [132] or low, i.e., with an H-score lower than or equal to the first quartile of the distribution. - 0.05) in the case of SIRT1 expression under the first quartile of the H-score distribution.. - In Supplemental Table 6, the differences in the immu- nohistochemical expression of TFEB, CARM1, and SIRT1 are reported, as well as the PMR value of the PITX2 methylation. - From this analysis of the role of the TFEB pathway in breast cancer chemoresistance, we reveal evidence that the increased expressions of TFEB and Beclin-1 are asso- ciated with a shorter survival period in patients suffering from invasive breast cancer who undergo chemotherapy.. - Furthermore, in the basal-like and HER2- enriched breast cancer subtypes, SIRT1 seems to have a lower H-score than in the luminal molecular subtypes.. - Meanwhile, in the basal-like and HER2-enriched breast cancer subtypes TFEB and Beclin-1 seem to have a higher H-score than in the luminal molecular subtypes.. - Furthermore, despite the effectiveness of screening with improved early diagnosis and the pro- gressive advance of systemic therapies, no reduction has been observed in the prevalence of metastatic breast cancer at the time of diagnosis [1, 5, 50]. - As for other malignancies, autophagy seems to have a fundamental function in breast cancer resistance to chemotherapy as well as hormonal therapy [7, 9]. - However, data explicitly related to breast cancer is extremely limited, especially regarding TFEB. - Regarding SIRT1, there are reports which describe a correlation between its in- creased expression and a poor prognosis in breast cancer [19, 20]. - Since the correlation between SIRT1 and TFEB disappears when we look exclusively at the basal-like breast cancer subtype, our data actually suggests a different role of SIRT1 in the luminal molecu- lar subtypes compared to that in the basal-like ones, al- though in both cases, a low expression of SIRT1 is predictive of a better prognosis.. - However, at the moment, only one article dem- onstrates a correlation between an increased TFEB ex- pression in early breast cancer and a poorer prognosis [56]. - Our results confirm that an increased immunohis- tochemical TFEB expression correlates with a less favor- able prognosis in women affected by breast cancer and treated with chemotherapy. - Regarding CARM1, its increased expression corresponds with a less favorable prognosis in breast cancer and with HER2-positive tumors [6, 57]. - However, the last two studies had an average follow-up below 65 months, and it is known that the majority of recurrences can occur within the first 72 months of follow-up, also considering low-risk breast cancer . - Further- more, Liu and coworkers found an increased expression of Beclin-1 in the tamoxifen-resistant breast cancer cell line [22]. - On the other hand, this correlation is lost in the case of the basal-like subtype, so that in the breast cancer luminal subtypes, we can deduce that both TFEB and CARM1 act in the same pathway, while this may not be true in the case of the basal-like mo- lecular subtype [15]. - Our preliminary data demonstrate a potential prognostic value of TFEB, SIRT1, and Beclin-1, likely for their role within autophagy regulation in patients affected by breast cancer and treated with anti-blastic therapy. - Prevalence, risk factors, and prognosis of peritoneal metastasis from breast cancer. - Applicability of the Notthingham prognostic index for predicting the survival of triple-negative invasive breast cancer in a single Italian center. - Clinicopathological characteristics and outcome of high grade breast cancer: our 9 years ’ experience. - Type of breast cancer diagnosis, screening, and survival. - Clin Breast Cancer.. - Expression and sub-cellular localization of an epigenetic regulator, co-activator arginine methyltransferase 1 (CARM1), is associated with specific breast cancer subtypes and ethnicity. - Autophagy and endocrine resistance in breast cancer. - Current approaches and future directions in the treatment of HER2-positive breast cancer. - Clinical development of mTOR inhibitors in breast cancer. - 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New surgical trends in breast cancer treatment: conservative interventions and oncoplastic breast surgery. - Influence of surgical margins on the outcome of breast cancer patients: a retrospective analysis. - Dual SIRT1 expression patterns strongly suggests its bivalent role in human breast cancer. - Transcription factor EB expression in early breast Cancer relates to lysosomal/Autophagosomal markers and prognosis. - Clin Breast Cancer. - Overexpression of CARM1 in breast cancer is correlated with poorly characterized clinicopathologic parameters and molecular subtypes. - The oestrogen receptor coactivator CARM1 has an oncogenic effect and is associated with poor prognosis in breast cancer. - predict poor prognosis of ER-positive, HER2-negative breast cancer. - Clinicopathologic correlation of beclin-1 and bcl-2 expression in human breast cancer. - Differences in autophagy-related activity by molecular subtype in triple-negative breast cancer. - Re-expression of ARHI (DIRAS3) induces autophagy in breast cancer cells and enhances the inhibitory effect of paclitaxel. - PITX2 DNA-methylation predicts response to anthracycline-based adjuvant chemotherapy in triple-negative breast cancer patients
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