In vitro studies of a prolactin antagonist, hPRL-G129R in human breast cancer cells.

Abstract

Human prolactin (hPRL) has been shown to be one of the important survival/growth factors that promotes the proliferation of breast cancer cells in an autocrine/paracrine manner. In our recent studies, we demonstrated that a hPRL antagonist with a single amino acid substitution mutation (hPRL-G129R) was able to inhibit breast cancer cell proliferation via induction of apoptosis (1). In this study three independent yet related experiments were carried out regarding the effects of hPRL-G129R in breast cancer cells. We investigated the possible mechanism(s) of hPRL-G129R induced apoptosis in breast cancer cells. It is well documented that transforming growth factors (TGF) in conjunction with hormones such as estrogen and PRL play a major role in modulating the proliferation and apoptosis of mammary cells. We first investigated the relationships between hPRL/hPRL-G129R and TGFs. We show that hPRL is able to down-regulate TGF beta 1 (apoptotic factor) secretion and up-regulate TGF alpha (survival factor) secretion in a dose-dependent manner in T-47D cells. More importantly the hPRL antagonist up-regulates TGF beta 1 and down-regulates TGF alpha secretion. When hPRL-G129R was applied together with hPRL, it blocked the effects of hPRL. Secondly, we tested the possible involvement of caspases in hPRL-G129R induced apoptosis. We have shown that caspase-3 is activated by hPRL-G129R at a concentration of 250 ng/ml in T-47D breast cancer cells. Thirdly, we explored the additive effects of an anti-neoplastic drug, cisplatin, with the hPRL-G129R in T47D breast cancer cells. We show that cisplatin and hPRL-G129R when applied together resulted in about 40% growth inhibition in T-47D cells.

• Authors: P Ramamoorthy, R Sticca, T E Wagner, W Y Chen
• Journal: International journal of oncology (Int J Oncol) Vol. 18 Issue 1 Pg. 25-32 (Jan 2001) ISSN: 1019-6439 [Print] Greece
• PMID: 11115535 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• TGFB1 protein, human
• Transforming Growth Factor alpha
• Transforming Growth Factor beta
• Transforming Growth Factor beta1
• Prolactin
• Arginine
• CASP3 protein, human
• Caspase 3
• Caspases
• Cisplatin
• Glycine

Topics

• Amino Acid Substitution
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Arginine (genetics)
• Breast Neoplasms (drug therapy, metabolism, pathology)
• Caspase 3
• Caspases (metabolism)
• Cell Division (drug effects)
• Cisplatin (pharmacology)
• Dose-Response Relationship, Drug
• Drug Synergism
• Enzyme Activation
• Female
• Glycine (genetics)
• Humans
• Point Mutation
• Prolactin (antagonists & inhibitors, genetics, pharmacology)
• Transforming Growth Factor alpha (metabolism)
• Transforming Growth Factor beta (metabolism)
• Transforming Growth Factor beta1
• Tumor Cells, Cultured