ResearchPad - novel-regulators-of-breast-cancer-progression https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[OR05-04 Steroid Receptor Co-Activators Complexes Cooperate with Progesterone Receptors (PR) to Reprogram Metabolic Pathways that Drive Therapy Resistant Populations in ER+ Breast Cancer]]> https://www.researchpad.co/article/elastic_article_6041 Late recurrence of metastatic disease stemming from acquired therapy resistance remains a significant health burden for women with ER+ breast cancer. Disseminated ER+ tumor cell populations can remain quiescent for years to decades, and contributing factors include breast cancer stem cells (CSCs), which are non-proliferative and frequently exist as a minority population in recurrent therapy-resistant tumors. Progesterone receptors (PR) are known drivers of normal stem and breast CSCs. Our objective was to define novel signaling pathways governing cell fate transitions involved in driving therapy resistance in ER+ breast cancer. We reported that cytoplasmic complexes composed of steroid receptor (SR) co-activators, PELP1 and SRC-3, drive breast CSC outgrowth. SRC-3 knockdown abrogated PELP1-induced CSC expansion and target genes required for cell survival, suggesting an essential role for PELP1/SRC-3 complexes. PELP1 also forms a signaling and transcriptional complex with ER and PR-B. Phospho-PR species are key mediators of stemness in ER+ breast cancer models. Accordingly, PR knockdown and antiprogestins disrupted PELP1/SRC-3 complexes and blocked PELP1-induced breast CSC outgrowth. Mammary stem cell (MaSC) populations were increased in vivo in MMTV-tTA;TRE-cyto-PELP1 transgenic mice as well as in MMTV-tTA;TRE-hPR-B mice. To better understand PELP1-mediated pathways, we performed RNA-seq on MCF-7 PELP1+ models grown in tumorsphere conditions to enrich for CSC populations (ALDH+, CD44+/CD24-). Cytoplasmic PELP1-expressing cells had a different global gene profile relative to WT PELP1 (i.e. nuclear). Gene sets associated with stem cell biology, hypoxic stress, and cancer metabolism were differentially regulated, including members of the glycolytic bi-functional kinase/phosphatase PFKFB family. Seahorse metabolic phenotyping demonstrated cytoplasmic PELP1 influences metabolism by increasing both glycolysis and mitochondrial respiration. Cytoplasmic PELP1 interacted strongly with PFKFB3 and PFKFB4, and inhibition of PFKFB3 or PFKFB4 kinase activity blocked PELP1-induced tumorspheres and protein-protein interactions with SRC-3. Additionally, antiprogestin and PFKFB inhibitors were synergistic when combined with ER+ targeted therapies. These aspects of PELP1/SRC-3 biology were phenocopied in therapy resistant models (tamoxifen resistant [TamR], paclitaxel resistant [TaxR]). Together, our data suggest that PELP1, SRC-3, PR, and PFKFBs form complexes that reprogram cellular metabolism to drive breast CSC expansion. Identifying the mechanisms that regulate recurrent ER+ tumor cell populations will enable specific targeting within heterogeneous breast tumors and may lead to the development of non-ER targets that can be used in combination with endocrine treatments to overcome therapy resistance.

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<![CDATA[OR05-01 Small Heterodimer Partner Modulates Antigen Presenting Myeloid Cells to Impair Regulatory T Cell Expansion, Promoting Anti-Tumor Immunity in Models of Breast Cancer]]> https://www.researchpad.co/article/elastic_article_5967 Immune checkpoint blockade has had underwhelming responses in breast cancer, in part due to the highly immune suppressive microenvironment. As a result, breast cancer continues to be the second most common cancer-related mortality amongst women, providing strong rationale for the development of new therapeutic approaches. Elevated circulating cholesterol is a poor prognostic, while breast cancer patients taking cholesterol-lowering drugs display increased time to recurrence. We and others have previously demonstrated that cholesterol metabolites mediate these effects by promoting breast cancer growth and metastasis, in part by suppressing the immune system. Therefore, given the demonstrated importance of cholesterol and its metabolites in breast cancer pathophysiology and immunology, we hypothesized that proteins involved in the regulation of cholesterol homeostasis would influence cancer progression. Through informatics analysis of breast tumors, we found that elevated expression of Small Heterodimer Partner (SHP; NR0B2) was a favorable prognostic. Antigen presenting cells such as macrophages and dendritic cells were found to express SHP, and manipulation of SHP altered the expression of genes involved in cross-talk with T cells. Intriguingly, when activated T cells were co-cultured with macrophages overexpressing SHP, there was a decrease in the expansion of regulatory T cells (Tregs) and vice versa in the absence of SHP. Adoptive transfer studies confirmed that loss of SHP resulted in immune suppressive Tregs. We hypothesized that myeloid cell-expressed SHP would promote immune surveillance and tumor clearance. In support of this hypothesis, tumors in the MMTV-PyMT model of mammary cancer grew at an accelerated rate in SHP-knockout mice. Tumors from these mice had significantly more Tregs and fewer effector T cells. Furthermore, orthotopic mammary tumor grafts grew at an increased rate in mice lacking SHP expression in myeloid cells (SHPfl/fl;LysMCre), compared to controls. A small molecule agonist of SHP impaired primary and metastatic tumor growth, and significantly enhanced the efficacy of immune checkpoint blockade in murine models of mammary cancer. Therefore, SHP represents a potential target to decrease suppressive Tregs, thereby allowing for immune-clearance of tumors.

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<![CDATA[OR05-05 Lethal ERα-Dependent Hyperactivation of the Unfolded Protein Response Induces Complete Regression Without Recurrence of Primary and Metastatic Breast Cancer]]> https://www.researchpad.co/article/N736bb37f-292a-488f-9a43-92546050465e 115,000 fold mean regression) in about 45% of mice (18/39). Although durable response for 4-6 months without additional treatment was common, tumors that did recur remained fully sensitive to ErSO re-treatment. Consistent with the essential nature of the UPR pathway targeted by ErSO, in more than 100 tumor-bearing mice, we have never seen an ErSO-resistant tumor. In just 7 days, oral ErSO induced complete regression of most lung, bone, and liver metastases. ErSO is well-tolerated in mice and blood-brain-barrier penetrant. Injected ErSO induced profound regression of challenging brain tumors. On average, ErSO-treated tumors were >180-fold smaller than vehicle-treated tumors. These xenograft studies used human cancer cells in mice that lack a functional immune system and therefore did not exploit the known ability of inducers of necrotic cell death to activate immune cells and induce immunogenic cell death. Notably, medium from breast cancer cells killed by ErSO contained high levels of immune cell activators, robustly activated mouse and human macrophages and increased macrophage migration. Moreover, use of ErSO is not limited to breast cancer. ErSO rapidly kills ERα positive ovarian and endometrial cancer cells that do not require estrogen for growth. ErSO’s potent activity against advanced primary and metastatic ERα-positive breast cancers represents a paradigm shift in leveraging ERα for anticancer efficacy. ]]> <![CDATA[OR05-02 The IGFBP-3/IGFBP-3 Receptor Axis Is a New Therapeutic Target for Triple Negative Breast Cancer]]> https://www.researchpad.co/article/N2f3c2028-fae3-49ae-b2f8-486cac90202e <![CDATA[OR05-06 The Androgen Receptor Is a Tumour Suppressor in Estrogen Receptor Positive Breast Cancer]]> https://www.researchpad.co/article/N792c2c35-7279-4b6f-b633-28674ee78b21