scholarly journals Minireview: Nuclear Receptors and Breast Cancer

2008 ◽  
Vol 22 (10) ◽  
pp. 2215-2228 ◽  
Author(s):  
Suzanne D. Conzen
Keyword(s):  
Breast Cancer ◽  
Growth Factor ◽  
Cell Growth ◽  
Epithelial Cell ◽  
Signaling Pathways ◽  
Cancer Biology ◽  
Progesterone Receptors ◽  
Growth Factor Signaling ◽  
Breast Cancers ◽  
Breast Cancer Patients

Abstract Until recently, the study of nuclear receptor (NR) function in breast cancer biology has been largely limited to estrogen and progesterone receptors. The development of reliable gene expression arrays, real-time quantitative RT-PCR, and immunohistochemical techniques for studying NR superfamily members in primary human breast cancers has now revealed the presence and potential importance of several additional NRs in the biology of breast cancer. These include receptors for steroid hormones (including androgens and corticosteroids), fat-soluble vitamins A and D, fatty acids, and xenobiotic lipids derived from diet. It is now clear that after NR activation, both genomic and nongenomic NR pathways can coordinately activate growth factor signaling pathways. Advances in our understanding of both NR functional networks and epithelial cell growth factor signaling pathways have revealed a frequent interplay between NR and epithelial cell growth factor family signaling that is clinically relevant to breast cancer. Understanding how growth factor receptors and their downstream kinases are activated by NRs (and vice-versa) is a central goal for maximizing treatment opportunities in breast cancer. In addition to the estrogen receptor, it is predicted that modulating the activity of other NRs will soon provide novel prevention and treatment approaches for breast cancer patients.

Biology of Progesterone Receptor Loss in Breast Cancer and Its Implications for Endocrine Therapy

2005 ◽  
Vol 23 (30) ◽  
pp. 7721-7735 ◽  
Author(s):  
Xiaojiang Cui ◽  
Rachel Schiff ◽  
Grazia Arpino ◽  
C. Kent Osborne ◽  
Adrian V. Lee
Keyword(s):  
Breast Cancer ◽  
Growth Factor ◽  
Progesterone Receptor ◽  
Signaling Pathways ◽  
Endocrine Therapy ◽  
Aromatase Inhibitors ◽  
Growth Factor Signaling ◽  
Breast Cancers ◽  
Estrogen Withdrawal ◽  
Er Positive

The response to endocrine therapy in breast cancer correlates with estrogen receptor (ER) and progesterone receptor (PR) status. ER-positive/PR-negative breast cancers respond less well to selective ER modulator (SERM) therapy than ER-positive/PR-positive tumors. The predictive value of PR has long been attributed to the dependence of PR expression on ER activity, with the absence of PR reflecting a nonfunctional ER and resistance to hormonal therapy. However, recent clinical and laboratory evidence suggests that ER-positive/PR-negative breast cancers may be specifically resistant to SERMs, whereas they may be less resistant to estrogen withdrawal therapy with aromatase inhibitors, which is a result inconsistent with the nonfunctional ER theory. Novel alternative molecular mechanisms potentially explaining SERM resistance in ER-positive/PR-negative tumors have been suggested by recent experimental indications that growth factors may downregulate PR levels. Thus, the absence of PR may not simply indicate a lack of ER activity, but rather may reflect hyperactive cross talk between ER and growth factor signaling pathways that downregulate PR even as they activate other ER functions. Therefore, ER-positive/PR-negative breast tumors might best be treated by completely blocking ER action via estrogen withdrawal with aromatase inhibitors, by targeted ER degradation, or by combined therapy targeting both ER and growth factor signaling pathways. In this review, we will discuss the biology and etiology of ER-positive/PR-negative breast cancer, highlighting recent data on molecular cross talk between ER and growth factor signaling pathways and demonstrating how PR might be a useful marker of these activities. Finally, we will consider the clinical implications of these observations.

scholarly journals A negative feedback loop between Insulin-like Growth Factor signaling and the lncRNA SNHG7 tightly regulates transcript levels and proliferation

2019 ◽  
Author(s):  
David N. Boone ◽  
Andrew Warburton ◽  
Sreeroopa Som ◽  
Adrian V. Lee
Keyword(s):  
Breast Cancer ◽  
Growth Factor ◽  
Cancer Patients ◽  
Transcriptional Response ◽  
Feedback Mechanism ◽  
Growth Factor Signaling ◽  
Breast Cancers ◽  
Breast Cancer Patients ◽  
Protein Coding ◽  
Protein Coding Genes

ABSTRACTEvidence suggests Insulin-like growth factor 1 (IGF1) signaling is involved in the initiation and progression of a subset of breast cancers by inducing cell proliferation and survival(1, 2). Although the signaling cascade following IGF1 receptor activation is well-studied(3, 4), the key elements of the transcriptional response governing IGF1’s actions are not well understood. Recent studies reveal that the majority of the genome is transcribed and that there are more long non-coding RNAs (lncRNAs) than protein coding genes(5), several of which are dysegulated in human cancer(6, 7). However, studies on the regulation and mechanism of action of these lncRNAs are in their infancy. Here we show that IGF1 alters the expression levels of a subset of lncRNAs. SNHG7, a member of the small nucleolar host gene family, is a highly-expressed lncRNA that is consistently and significantly down-regulated by IGF1 signaling by a post-transcriptional mechanism through the MAPK pathway. SNHG7 regulates proliferation of breast cancer cell lines in a dose-dependent manner, and silencing SNHG7 expression causes cell cycle arrest in G0/G1. Intriguingly, SNHG7 alters the expression of many IGF1 signaling intermediates and IGF1-regulated genes suggesting a feedback mechanism to tightly regulate the IGF1 response. Finally, we show with TCGA data that SNHG7 is overexpressed in tumors of a subset of breast cancer patients and that these patients have lower disease-free survival than patients without elevated SNHG7 expression. We propose that SNHG7 is a lncRNA oncogene that is controlled by growth factor signaling in a feedback mechanism to prevent hyperproliferation, and that this regulation can be lost in the development or progression of breast cancer.SIGNIFICANCE STATEMENTIGF1 signaling drives proliferation and survival and is important for the initiation and development of a subset of breast cancers. IGF1 is known to control the expression of thousands of protein coding genes, but it is unknown if it alters the expression of other gene types, such as long noncoding RNAs. Here we demonstrate that IGF regulates lncRNAs including the mostly unstudied SNHG7. We further show that SNHG7 is necessary for proliferation and modulates IGF1 signaling through a novel feedback mechanism that is required for fine-tuning of the transcriptional response to growth factor signaling and proliferation of breast cancer cells. SNHG7 is highly expressed in a subset of breast cancer patients with poor prognosis giving further credence that it is a novel oncogene.

scholarly journals JARID1A and IGF2R are concomitantly up-regulated in trastuzumab-treated human breast cancers.

2020 ◽  
Author(s):  
Shahan Mamoor
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Growth Factor ◽  
Expression Profiles ◽  
Regulation Of Gene Expression ◽  
Metastatic Breast ◽  
Growth Factor Signaling ◽  
Breast Cancers ◽  
Breast Cancer Patients ◽  
Primary Tumors

Epigenetic regulation of gene expression is a mechanism by which signals transduced at the plasma membrane be can translated into differences in mRNA quantity and gene product at the protein level (1, 2). Trastuzumab is widely utilized for the treatment of adjuvant and metastatic breast cancer (3). We found, using analysis of public microarray and published multiplexed gene expression data (4, 5), that the histone lysine H3K4 demethylase JARID1A was among the genes whose expression was most significantly different when comparing the global gene expression profiles of trastuzumab-treated breast cancers and breast cancers not treated with trastuzumab. Expression of JARID1A in cancer cells has been associated with a drug-tolerant state with reduced drug sensitivity, dependent on insulin-like growth factor (IGF) signaling (6). Interestingly, we found that IGF2R was also among the genes whose expression was most significantly different transcriptome-wide when comparing the primary tumors of breast cancer patients treated with trastuzumab or not. These data clearly demonstrate up-regulation of a receptor for key growth factor signaling and together suggest that trastuzumab could be hard-wiring tumor cells for drug resistance.

Resistance to endocrine therapy in breast cancer: exploiting estrogen receptor/growth factor signaling crosstalk

2006 ◽  
Vol 13 (Supplement_1) ◽  
pp. S15-S24 ◽  
Author(s):  
Suleiman Massarweh ◽  
Rachel Schiff
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Growth Factor ◽  
Endocrine Therapy ◽  
Acquired Resistance ◽  
Growth Factor Signaling ◽  
Breast Cancer Patients ◽  
Signaling Crosstalk ◽  
Receptor Modulator ◽  
Signal Transduction Inhibitors

Targeting the estrogen receptor (ER) is the oldest form of molecular targeted therapy, and the widespread use of the selective estrogen receptor modulator tamoxifen in breast cancer is responsible for major improvements in cure rates, quality of life, and disease prevention in the last 25 years. Newer forms of endocrine therapy now available for the management of endocrine responsive breast cancer include a new generation of aromatase inhibitors, which lower the estrogen ligand for ER, and pure ER antagonists which destroy the receptor. Despite these recent clinical advances, intrinsic and acquired resistance to these endocrine therapies is still a common feature that limits the success of this therapeutic strategy. Recent research into the molecular biology of ER signaling has revealed a remarkably complex interactive signaling with other growth factor signaling pathways in breast cancer cells, potentially explaining some of the reasons behind endocrine therapy action as well as resistance. This view of a more complex ER signaling system has uncovered new molecular targets which, if present in a cancer cell, might be additionally targeted using various signal transduction inhibitors to overcome or prevent resistance to endocrine therapy. In addition, the dynamic inverse relationship between the expression of ER and growth factor receptors brings more excitement to the potential of restoring ER expression in apparently ER-negative cells by inhibition of growth factor signaling. Ongoing clinical trials of endocrine therapy combined with growth factor pathway inhibitors or their downstream signaling elements promise to further improve the present care for breast cancer patients.

scholarly journals Nexus Between PI3K/AKT and Estrogen Receptor Signaling in Breast Cancer

2020 ◽  
Author(s):  
Aditi Khatpe ◽  
Adedeji Adebayo ◽  
Christopher Herodotou ◽  
Brijesh Kumar ◽  
Harikrishna Nakshatri
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Estrogen Receptor ◽  
Growth Factor ◽  
Estrogen Receptor Alpha ◽  
Estrogen Therapy ◽  
Mtor Inhibitors ◽  
Growth Factor Signaling ◽  
Breast Cancers ◽  
Cell Cycle Machinery

Signaling from estrogen receptor alpha (ER) and its ligand estradiol (E2) is critical for growth of ~70% of breast cancers. Therefore, several drugs that inhibit ER functions are in clinical use for decades and new classes of anti-estrogens are continuously being developed. Although a significant number of ER+ breast cancers respond to anti-estrogen therapy, ~30% of these breast cancers recur, sometimes even after 20 years of initial diagnosis. Mechanism of resistance to anti-estrogens is one of the intensely studied disciplines in breast cancer. Several mechanisms have been proposed including mutations in ESR1, crosstalk between growth factor and ER signaling, and interplay between cell cycle machinery and ER signaling. ESR1 mutations as well as crosstalk with other signaling networks lead to ligand independent activation of ER thus rendering anti-estrogens ineffective, particularly when treatment involved anti-estrogens that do not degrade ERa. As a result of these studies, several therapies that combine anti-estrogens that degrade ER with PI3K/AKT/mTOR inhibitors targeting growth factor signaling or CDK4/6 inhibitors targeting cell cycle machinery are used clinically to treat recurrent ER+ breast cancers. In this review, we discuss nexus between ER-PI3K/AKT/mTOR pathways and how understanding of this nexus has helped to develop combination therapies.

PIK3CA mutations in breast cancer: A potential predictive marker

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 639-639
Author(s):  
M. Santarpia ◽  
G. Altavilla ◽  
M. Margeli ◽  
M. Mesiti ◽  
V. Cavallari ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Hormone Receptors ◽  
Detection System ◽  
Progesterone Receptors ◽  
Predictive Marker ◽  
Breast Cancer Cell Lines ◽  
Breast Cancers ◽  
Breast Cancer Patients ◽  
Sequence Detection ◽  
Pik3ca Mutations

639 Background: Somatic mutations in phosphoinositide-3-kinase catalytic alpha (PIK3CA) activates Akt, attenuates apoptosis and promotes tumor invasion. The common mutations E545K and H1047R confer resistance to paclitaxel in immortalized breast cancer cell lines. We screened primary breast cancers for PIK3CA mutations in the helical and catalytic domains. Methods: Tumor samples from 61 stage I-III breast cancer patients treated with adjuvant chemo- and/or hormone therapy were examined for PIK3CA mutations E542K, E545K and H1047R by the 5-nuclease assay (TaqMan) using the ABI Prism 7900HT Sequence Detection System. Results: Mutations were found in 17 patients (27.9%): 6 E542K; 5 E545K; 6 H1047R. PIK3CA mutations were not associated with expression of estrogen or progesterone receptors, lymph node metastases, or ERBB2 overexpression. (See table ) Conclusions: PIK3CA mutations occur frequently in breast cancer and could be a novel predictive marker of chemoresistance and an appealing target for therapeutic inhibition, independent of hormone receptors and ERBB2 status. [Table: see text] No significant financial relationships to disclose.

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