Chemotherapy is the mainstay treatment for advanced breast cancer, but tumor resistance is a major obstacle that results in treatment failure. Resistance results from many causes, including drug efflux, inactivation, altered expression of pro/anti-apoptotic proteins or tumor suppressor genes, and increased DNA repair mechanisms. We present evidence that prolactin (PRL) serves as a survival factor which antagonizes the cytotoxicity of the DNA-damaging agents cisplatin and doxorubicin, and the microtubule disrupting agent taxol. PRL protects breast cancer cells (BCC) against drugs by activating the detoxification enzyme glutathione-S-transferase (GST) as well as by increasing the expression of the anti- apoptotic protein Bcl-2. The human breast receives PRL input from two sources: the pituitary and local. Within the breast, stromal adipocytes produce significantly more PRL than epithelial cells, and both are under tonic inhibition. We discovered expression of dopamine receptors (DAR) in breast tissue, adipocytes and BCC. Similar to their action on pituitary PRL, dopamine and bromocriptine (Br) suppress breast PRL production. Locally- produced PRL likely confers chemoresistance, since BCC with high endogenous PRL are more resistant to drugs than those with low PRL. Our newly developed LS14 human adipocyte cell line, which produces PRL and expresses the PRL receptor (PRL-R), is also resistant to many anticancer drugs. Hypothesis: PRL confers chemoresistance against different classes of anti-cancer drugs by activating detoxification enzymes, anti-apoptotic proteins or both. Input of PRL to breast tumors comes from the circulation (pituitary), paracrine (stromal adipocytes) and autocrine (BCC). Similar to its action on the pituitary, dopamine suppresses breast PRL and thus sensitizes breast cancer to anticancer drugs.
Aim 1 : To compare expression of PRL and PRL-R in BCC at both the mRNA and proteins levels, and use knockdown and overexpression to determine the role of local PRL in chemoresistance, Aim 2: To examine whether GST and/or Bcl-2 mediate chemoresistance by PRL against four classes of drugs: DNA-damaging, microtubule altering, anti-metabolites, and the death ligand TRAIL (tumor necrotic factor (TNF)-related apoptosis-inducing ligand).
Aim 3 : To characterize DAR in adipocytes, BCC and LS14 cells, and determine whether dopamine and its agonists suppress PRL production and increase cell sensitivity to anticancer drugs.
Aim 4 : To establish mixed-cultures of fully differentiated LS14 adipocytes and BCC and examine whether dopamine agonists sensitize LS14/BCC tumors in athymic mice to anticancer drugs. Clinical Impact: Oral dopamine agonists with an excellent record of safety and efficacy for suppressing PRL are FDA-approved. Their use in breast cancer patients undergoing chemotherapy should improve dru efficacy, lower the doses, reduce side effects and expand the choice of effective drugs.

Public Health Relevance

This continuation study examines the mechanism by which prolactin, a hormone which is produced by both the pituitary gland and breast tissue, confers chemoresistance on breast cancer cells under in vitro and in vivo conditions. The long term goal is to establish FDA-approved, long acting dopamine agonists as suppressor or PRL secretion, resulting in increased efficacy of chemotherapeutic agents in breast cancer patients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA096613-09
Application #
8305713
Study Section
Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
Program Officer
Sathyamoorthy, Neeraja
Project Start
2002-07-01
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
9
Fiscal Year
2012
Total Cost
$243,918
Indirect Cost
$88,556
Name
University of Cincinnati
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
041064767
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
Ben-Jonathan, Nira; Hugo, Eric R (2016) Bisphenols Come in Different Flavors: Is ""S"" Better Than ""A""? Endocrinology 157:1321-3
Tuttle, Traci R; Mierzwa, Michelle L; Wells, Susanne I et al. (2016) The cyclic GMP/protein kinase G pathway as a therapeutic target in head and neck squamous cell carcinoma. Cancer Lett 370:279-85
Ben-Jonathan, Nira; Hugo, Eric (2015) Prolactin (PRL) in adipose tissue: regulation and functions. Adv Exp Med Biol 846:1-35
Tuttle, Traci R; Hugo, Eric R; Tong, Wilson S et al. (2014) Placental lactogen is expressed but is not translated into protein in breast cancer. PLoS One 9:e87325
Lo, Yuan-Hung; Ho, Po-Chun; Chen, Min-Shan et al. (2013) Phosphorylation at tyrosine 114 of Proliferating Cell Nuclear Antigen (PCNA) is required for adipogenesis in response to high fat diet. Biochem Biophys Res Commun 430:43-8
Cifuentes, Mariana; Fuentes, Cecilia; Tobar, Nicolas et al. (2012) Calcium sensing receptor activation elevates proinflammatory factor expression in human adipose cells and adipose tissue. Mol Cell Endocrinol 361:24-30
Idelman, Gila; Jacobson, Eric M; Tuttle, Traci R et al. (2011) Lactogens and estrogens in breast cancer chemoresistance. Expert Rev Endocrinol Metab 6:411-422
Borcherding, Dana C; Hugo, Eric R; Idelman, Gila et al. (2011) Dopamine receptors in human adipocytes: expression and functions. PLoS One 6:e25537
Jacobson, Eric M; Hugo, Eric R; Borcherding, Dana C et al. (2011) Prolactin in breast and prostate cancer: molecular and genetic perspectives. Discov Med 11:315-24
LaPensee, Elizabeth W; LaPensee, Christopher R; Fox, Sejal et al. (2010) Bisphenol A and estradiol are equipotent in antagonizing cisplatin-induced cytotoxicity in breast cancer cells. Cancer Lett 290:167-73

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