More Like this

1. Genome-Wide Analysis Unveils DNA Helicase RECQ1 as a Regulator of Estrogen Response Pathway in Breast Cancer Cells

   https://doi.org/10.1128/MCB.00515-20  

   Lu, Xing; Redon, Christophe E.; Tang, Wei; Parvathaneni, Swetha; Bokhari, Bayan; Debnath, Subrata; Li, Xiao Ling; Muys, Bruna R.; Song, Young; Pongor, Lorinc S.; et al (March 2021, Molecular and Cellular Biology)

   null (Ed.)

   ABSTRACT Susceptibility to breast cancer is significantly increased in individuals with germ line mutations in RECQ1 (also known as RECQL or RECQL1 ), a gene encoding a DNA helicase essential for genome maintenance. We previously reported that RECQ1 expression predicts clinical outcomes for sporadic breast cancer patients stratified by estrogen receptor (ER) status. Here, we utilized an unbiased integrative genomics approach to delineate a cross talk between RECQ1 and ERα, a known master regulatory transcription factor in breast cancer. We found that expression of ESR1 , the gene encoding ERα, is directly activated by RECQ1. More than 35% of RECQ1 binding sites were cobound by ERα genome-wide. Mechanistically, RECQ1 cooperates with FOXA1, the pioneer transcription factor for ERα, to enhance chromatin accessibility at the ESR1 regulatory regions in a helicase activity-dependent manner. In clinical ERα-positive breast cancers treated with endocrine therapy, high RECQ1 and high FOXA1 coexpressing tumors were associated with better survival. Collectively, these results identify RECQ1 as a novel cofactor for ERα and uncover a previously unknown mechanism by which RECQ1 regulates disease-driving gene expression in ER-positive breast cancer cells. 

   more » « less
2. In Silico Elucidation of the Plausible Inhibitory Potential of Withaferin A of Withania Somnifera Medicinal Herb Against Breast Cancer Targeting Estrogen Receptor

   https://doi.org/10.2174/1389201021666200129121843  

   Ali, Mohammad A.; Farah, Mohammad Abul; Al-Anazi, Khalid M.; Basha, Syed H.; Bai, Fang; Lee, Joongku; Al-Hemaid, Fahad M.A.; Mahmoud, Ahmed H.; Hailan, Waleed A.Q. (June 2020, Current Pharmaceutical Biotechnology)

   null (Ed.)

   Background: Estrogen Receptors (ER) are members of the nuclear intracellular receptorsfamily. ER once activated by estrogen, it binds to DNA via translocating into the nucleus and regulatesthe activity of various genes. Withaferin A (WA) - an active compound of a medicinal plant Withaniasomnifera was reported to be a very effective anti-cancer agent and some of the recent studies hasdemonstrated that WA is capable of arresting the development of breast cancer via targeting estrogenreceptor. Objective: The present study is aimed at understanding the molecular level interactions of ER and Tamoxifenin comparison to Withaferin A using In-silico approaches with emphasis on Withaferin Abinding capability with ER in presence of point mutations which are causing de novo drug resistance toexisting drugs like Tamoxifen. Methods: Molecular modeling and docking studies were performed for the Tamoxifen and WithaferinA with the Estrogen receptor. Molecular docking simulations of estrogen receptor in complex withTamoxifen and Withaferin A were also performed. Results: Amino acid residues, Glu353, Arg394 and Leu387 was observed as crucial for binding andstabilizing the protein-ligand complex in case of Tamoxifen and Withaferin-A. The potential ofWithaferin A to overcome the drug resistance caused by the mutations in estrogen receptor to the existingdrugs such as Tamoxifen was demonstrated. Conclusion: In-silico analysis has elucidated the binding mode and molecular level interactions whichare expected to be of great help in further optimizing Withaferin A or design / discovery of futurebreast cancer inhibitors targeting estrogen receptor. 

   more » « less
3. Targeting the Interplay between Epithelial-to-Mesenchymal-Transition and the Immune System for Effective Immunotherapy

   https://doi.org/10.3390/cancers11050714  

   Soundararajan, Rama; Fradette, Jared; Konen, Jessica; Moulder, Stacy; Zhang, Xiang; Gibbons, Don; Varadarajan, Navin; Wistuba, Ignacio; Tripathy, Debasish; Bernatchez, Chantale; et al (May 2019, Cancers)

   Over the last decade, both early diagnosis and targeted therapy have improved the survival rates of many cancer patients. Most recently, immunotherapy has revolutionized the treatment options for cancers such as melanoma. Unfortunately, a significant portion of cancers (including lung and breast cancers) do not respond to immunotherapy, and many of them develop resistance to chemotherapy. Molecular characterization of non-responsive cancers suggest that an embryonic program known as epithelial-mesenchymal transition (EMT), which is mostly latent in adults, can be activated under selective pressures, rendering these cancers resistant to chemo- and immunotherapies. EMT can also drive tumor metastases, which in turn also suppress the cancer-fighting activity of cytotoxic T cells that traffic into the tumor, causing immunotherapy to fail. In this review, we compare and contrast immunotherapy treatment options of non-small cell lung cancer (NSCLC) and triple negative breast cancer (TNBC). We discuss why, despite breakthrough progress in immunotherapy, attaining predictable outcomes in the clinic is mostly an unsolved problem for these tumors. Although these two cancer types appear different based upon their tissues of origin and molecular classification, gene expression indicate that they possess many similarities. Patient tumors exhibit activation of EMT, and resulting stem cell properties in both these cancer types associate with metastasis and resistance to existing cancer therapies. In addition, the EMT transition in both these cancers plays a crucial role in immunosuppression, which exacerbates treatment resistance. To improve cancer-related survival we need to understand and circumvent, the mechanisms through which these tumors become therapy resistant. In this review, we discuss new information and complementary perspectives to inform combination treatment strategies to expand and improve the anti-tumor responses of currently available clinical immune checkpoint inhibitors. 

   more » « less
4. A Pooled Case-only Analysis of Reproductive Risk Factors and Breast Cancer Subtype Among Black Women in the Southeastern United States

   14. Sanderson, M; Pal, T; Beeghly-Fadiel, A; Fadden, M. K; Dujon, S. A; Clinton, C; Jimenez, C; Davis, J; Fortune, M; Thompson, J; et al (July 2021, Cancer epidemiology biomarkers prevention)

   Background: We investigated the association between reproductive risk factors and breast cancer subtype in Black women. On the basis of the previous literature, we hypothesized that the relative prevalence of specific breast cancer subtypes might differ according to reproductive factors. Methods: We conducted a pooled analysis of 2,188 (591 premenopausal, 1,597 postmenopausal) Black women with a primary diagnosis of breast cancer from four studies in the southeastern United States. Breast cancers were classified by clinical subtype. Case-only polytomous logistic regression models were used to estimate ORs and 95% confidence intervals (CI) for HER2+ and triple-negative breast cancer (TNBC) status in relation to estrogen receptor–positive (ER+)/HER2− status (referent) for reproductive risk factors. Results: Relative to women who had ER+/HER2− tumors, women who were age 19–24 years at first birth (OR, 1.78; 95% CI, 1.22–2.59) were more likely to have TNBC. Parous women were less likely to be diagnosed with HER2+ breast cancer and more likely to be diagnosed with TNBC relative to ER+/HER2− breast cancer. Postmenopausal parous women who breastfed were less likely to have TNBC [OR, 0.65 (95% CI, 0.43–0.99)]. Conclusions: This large pooled study of Black women with breast cancer revealed etiologic heterogeneity among breast cancer subtypes. Impact: Black parous women who do not breastfeed are more likely to be diagnosed with TNBC, which has a worse prognosis, than with ER+/HER2− breast cancer. 

   more » « less
5. Cell cycle plasticity underlies fractional resistance to palbociclib in ER+/HER2− breast tumor cells

   https://doi.org/10.1073/pnas.2309261121  

   Zikry, Tarek M.; Wolff, Samuel C.; Ranek, Jolene S.; Davis, Harris M.; Naugle, Ander; Luthra, Namit; Whitman, Austin A.; Kedziora, Katarzyna M.; Stallaert, Wayne; Kosorok, Michael R.; et al (February 2024, Proceedings of the National Academy of Sciences)

   The CDK4/6 inhibitor palbociclib blocks cell cycle progression in Estrogen receptor–positive, human epidermal growth factor 2 receptor–negative (ER+/HER2−) breast tumor cells. Despite the drug’s success in improving patient outcomes, a small percentage of tumor cells continues to divide in the presence of palbociclib—a phenomenon we refer to as fractional resistance. It is critical to understand the cellular mechanisms underlying fractional resistance because the precise percentage of resistant cells in patient tissue is a strong predictor of clinical outcomes. Here, we hypothesize that fractional resistance arises from cell-to-cell differences in core cell cycle regulators that allow a subset of cells to escape CDK4/6 inhibitor therapy. We used multiplex, single-cell imaging to identify fractionally resistant cells in both cultured and primary breast tumor samples resected from patients. Resistant cells showed premature accumulation of multiple G1 regulators including E2F1, retinoblastoma protein, and CDK2, as well as enhanced sensitivity to pharmacological inhibition of CDK2 activity. Using trajectory inference approaches, we show how plasticity among cell cycle regulators gives rise to alternate cell cycle “paths” that allow individual tumor cells to escape palbociclib treatment. Understanding drivers of cell cycle plasticity, and how to eliminate resistant cell cycle paths, could lead to improved cancer therapies targeting fractionally resistant cells to improve patient outcomes. 

   more » « less