Dopamine Receptors in Breast Cancer: Prevalence, Signaling, and Therapeutic Applications.

Breast cancer (BC) is the most common malignancy among women, with over one million cases occurring annually worldwide. Although therapies against estrogen receptors and HER2 have improved response rate and survival, patients with advanced disease, who are resistant to anti-hormonal therapy and/or to chemotherapy, have limited treatment options for reducing morbidity and mortality. These limitations provide major incentives for developing new, effective, and personalized therapeutic interventions.

Suppression of Breast Cancer by Small Molecules That Block the Prolactin Receptor.

Prolactin (PRL) is a protein hormone which in humans is secreted by pituitary lactotrophs as well as by many normal and malignant non-pituitary sites. Many lines of evidence demonstrate that both circulating and locally produced PRL increase breast cancer (BC) growth and metastases and confer chemoresistance. Our objective was to identify and then characterize small molecules that block the tumorigenic actions of PRL in BC.

Activation of the cGMP/protein kinase G system in breast cancer by the dopamine receptor-1.

Despite recent advances in the detection and treatment of breast cancer, many shortcomings remain, providing incentives to search for new therapeutic targets. This review provides information on the expression and actions of dopamine receptor-1 (D1R) in breast cancer. D1R is overexpressed in a significant number of primary breast tumors, characterized by having an aggressive phenotype and predicting a shorter survival time for patients.

Soluble guanylate cyclase stimulators increase sensitivity to cisplatin in head and neck squamous cell carcinoma cells.

Head and neck squamous cell carcinoma (HNSCC) is an aggressive and often fatal disease. Cisplatin is the most common chemotherapeutic drug in the treatment of HNSCC, but intrinsic and acquired resistance are frequent, and severe side effects occur at high doses. The second messenger cyclic GMP (cGMP) is produced by soluble guanylate cyclase (sGC).

The cyclic GMP/protein kinase G pathway as a therapeutic target in head and neck squamous cell carcinoma.

Head and neck squamous cell carcinoma (HNSCC) is an aggressive disease with high mortality. Treatments, which can result in significant morbidity, have not substantially changed in three decades. The second messenger cyclic GMP (cGMP), which targets protein kinase G (PKG), is generated by guanylate cyclases (GCs), and is rapidly hydrolyzed by phosphodiesterases (PDEs).

Expression and therapeutic targeting of dopamine receptor-1 (D1R) in breast cancer.

Patients with advanced breast cancer often fail to respond to treatment, creating a need to develop novel biomarkers and effective therapeutics. Dopamine (DA) is a catecholamine that binds to five G protein-coupled receptors. We discovered expression of DA type-1 receptors (D1Rs) in breast cancer, thereby identifying these receptors as novel therapeutic targets in this disease.

Knockdown of the Inhibitor of Apoptosis BRUCE Sensitizes Resistant Breast Cancer Cells to Chemotherapeutic Agents.

Background And Objectives: Management of patients with breast cancer often fails because of inherent or acquired resistance to chemotherapy. BRUCE (BIR repeat containing ubiquitin-conjugating enzyme) is a member of the inhibitor of apoptosis protein (IAP) family. It has various cellular functions including suppression of apoptosis and promotion of cytokinesis.

Prolactin (PRL) in adipose tissue: regulation and functions.

New information concerning the effects of prolactin (PRL) on metabolic processes warrants reevaluation of its overall metabolic actions. PRL affects metabolic homeostasis by regulating key enzymes and transporters associated with glucose and lipid metabolism in several target organs. In the lactating mammary gland, PRL increases the production of milk proteins, lactose, and lipids.

Minireview: Extrapituitary prolactin: an update on the distribution, regulation, and functions.

Prolactin (PRL) is an important hormone with many diverse functions. Although it is predominantly produced by lactrotrophs of the pituitary there are a number of other organs, cells, and tissues in which PRL is expressed and secreted. The impact of this extrapituitary PRL (ePRL) on localized metabolism and cellular functions is gaining widespread attention.

Placental lactogen is expressed but is not translated into protein in breast cancer.

Introduction: Several studies reported that the pregnancy-specific hormone placental lactogen (hPL) is expressed at both mRNA and protein levels in breast cancer. The overall objective was to establish hPL, the product of the CSH1 and CSH2 genes, as a biomarker for breast cancer.

Methods: CSH expression was determined at the mRNA level in breast cancer cell lines (BCC) and primary carcinomas by real-time and conventional PCR and the products verified as CSH1 by sequencing.

Adipogenic effect of calcium sensing receptor activation.

We established that human adipose cells and the human adipose cell line LS14 express the calcium-sensing receptor (CaSR) and that its activation induces inflammatory cytokine production. Also, its expression is enhanced upon exposure to obesity-associated proinflammatory cytokines. We have thus proposed that CaSR activation may be associated with adipose dysfunction.

Phosphorylation at tyrosine 114 of Proliferating Cell Nuclear Antigen (PCNA) is required for adipogenesis in response to high fat diet.

Clonal proliferation is an obligatory component of adipogenesis. Although several cell cycle regulators are known to participate in the transition between pre-adipocyte proliferation and terminal adipocyte differentiation, how the core DNA synthesis machinery is coordinately regulated in adipogenesis remains elusive. PCNA (Proliferating Cell Nuclear Antigen) is an indispensable component for DNA synthesis during proliferation.

Calcium sensing receptor activation elevates proinflammatory factor expression in human adipose cells and adipose tissue.

The proinflammatory status of adipose tissue has been linked to the metabolic and cardiovascular consequences of obesity. Human adipose cells express the calcium sensing receptor (CaSR), and its expression is elevated in inflammatory states, such as that associated with obesity. Given the CaSR's association with inflammation in other tissues, we evaluated its role elevating the adipose expression of inflammatory factors.

Dopamine receptors in human adipocytes: expression and functions.

Introduction: Dopamine (DA) binds to five receptors (DAR), classified by their ability to increase (D1R-like) or decrease (D2R-like) cAMP. In humans, most DA circulates as dopamine sulfate (DA-S), which can be de-conjugated to bioactive DA by arylsulfatase A (ARSA). The objective was to examine expression of DAR and ARSA in human adipose tissue and determine whether DA regulates prolactin (PRL) and adipokine expression and release.

Lactogens and estrogens in breast cancer chemoresistance.

Tumor resistance to chemotherapy in advanced breast cancer is a major impediment to treatment success. Resistance can be induced by the drugs themselves or result from the action of internal factors. The role of hormones in chemoresistance has received little attention.

Prolactin in breast and prostate cancer: molecular and genetic perspectives.

Prostate and breast cancers affect millions of men and women, respectively. Advanced forms of the disease, which can no longer be controlled by hormonal disruption or chemotherapy, have very limited treatment options. Consequently, there is a major benefit to identify new targets for therapy in both types of cancer.

Unexploited therapies in breast and prostate cancer: blockade of the prolactin receptor.

Breast and prostate cancers are hormone-sensitive malignancies that afflict millions of women and men. Although prolactin (PRL) is known as a survival factor that supports tumor growth and confers chemoresistance in both cancers, its precise role in these tumors has not been studied extensively. Growth hormone and placental lactogen also bind PRL receptor (PRLR) and mimic some of the actions of PRL.

Obesity-associated proinflammatory cytokines increase calcium sensing receptor (CaSR) protein expression in primary human adipocytes and LS14 human adipose cell line.

Obesity-associated health complications are thought to be in part due to the low-grade proinflammatory state that characterizes this disease. The calcium sensing receptor (CaSR), which is expressed in human adipose cells, plays an important role in diseases involving inflammation. To assess the relevance of this protein in adipose pathophysiology, we evaluated its expression in adipocytes under obesity-related proinflammatory conditions.

Selective estrogen receptor down-regulator and selective estrogen receptor modulators differentially regulate lactotroph proliferation.

Background: We recently reported that estrogen receptor alpha (ERalpha), even in absence of estrogen (E2), plays a critical role in lactotroph homeostasis. The anti-estrogen ICI 182780 (ICI), but not tamoxifen or raloxifene, rapidly promoted the degradation of ERalpha, and inhibited cell proliferation. However, all three ER antagonists suppressed PRL release, suggesting that receptor occupation is sufficient to inhibit prl gene expression whereas receptor degradation is required to suppress lactotroph proliferation.

Bisphenol A and estradiol are equipotent in antagonizing cisplatin-induced cytotoxicity in breast cancer cells.

Resistance to chemotherapy is a major problem facing breast cancer patients. Cisplatin, a highly effective DNA-damaging drug, has shown only little success in breast cancer treatment. We are reporting that low nanomolar doses of bisphenol A (BPA) or estradiol antagonize cisplatin cytotoxicity in breast cancer cells, with their effects not mediated via classical estrogen receptors.

Epidermal growth factor receptor cross-talks with ligand-occupied estrogen receptor-alpha to modulate both lactotroph proliferation and prolactin gene expression.

Both estrogen (E2) and EGF regulate lactotrophs, and we recently demonstrated that EGF phosphorylates S118 on estrogen receptor-alpha (ERalpha) and requires ERalpha to stimulate prolactin (PRL) release. However, the interactions between ligand-occupied ERalpha and activated ErbB1 and its impact on lactotroph function are unknown. Using rat GH3 lactotrophs, we found that both E2 and EGF independently stimulated proliferation and PRL gene expression.

Prolactin confers resistance against cisplatin in breast cancer cells by activating glutathione-S-transferase.

Resistance to chemotherapy is a major obstacle for successful treatment of breast cancer patients. Given that prolactin (PRL) acts as an anti-apoptotic/survival factor in the breast, we postulated that it antagonizes cytotoxicity by chemotherapeutic drugs. Treatment of breast cancer cells with PRL caused variable resistance to taxol, vinblastine, doxorubicin and cisplatin.

Effects of bisphenol A on adipokine release from human adipose tissue: Implications for the metabolic syndrome.

Bisphenol A (BPA) is one of the most prevalent and best studied endocrine disruptors. After years of exposure to consumer products containing BPA, most individuals tested have circulating BPA at the low nanomolar levels. In addition to its well documented actions on the reproductive system, BPA exerts a wide variety of metabolic effects.