EVALUATION OF HUMAN PROLACTIN, ITS ANTAGONIST, AND ANTAGONIST-BASED FUSION PROTEINS AS CHEMOPREVENTATIVE AND THERAPEUTIC AGENTS

Cancer is a collection of diseases with many different manifestations and is the second leading cause of death in the United States. Breast cancer accounts for nearly one third of cancer diagnosis in women. Prolactin (PRL) functions as a lactogen and as a mammary gland differentiation factor. PRL acts in an autocrine/paracrine manner within the mammary gland and in breast tumors which implies PRL may be involved in breast cancer progression. This is corroborated by the PRLR over-expression in breast cancer cells lines and the majority of patient biopsies. These reasons make PRL and PRLR attractive targets for breast cancer treatment and prevention. Transgenic mice expressing hPRL or G129R, under the regulation of the metallothionein (Mt) promoter, were fed a chemical carcinogen, 9,10-Dimethyl-1,2-benzanthracene (DMBA). G129R transgenic mice exhibited decreased growth rate of chemically-induced tumors, while hPRL transgenic mice had an increased cancer rate. Microarray analysis revealed that hPRL transgenic mammary gland showed an expression pattern similar to those of a pregnant mouse, while the G129R transgenic gland revealed an increase in various apoptotic markers. Previously, fusion proteins composed of a PRLR antagonist (G129R) and anti-tumor domains were developed; these included fusions with an angiogenesis inhibitor (Endostatin), an immune system modulator (interleukin-2), and a cytotoxin (PE38KDEL). The rationale was that each fusion protein would target the mammary gland via the G129R moiety and attack different hallmarks common to tumor cells via the second moiety. A novel clinically-relevant model was generated by surgically removing spontaneous mammary tumors from MMTV-neu transgenic mice and monitoring tumor recurrence while treating with the fusion protein cocktail. Tumor recurrence was significantly delayed in groups treated with the fusion proteins in comparison to the control group. In conclusion, targeting multiple hallmarks of cancer using a combination of dual function therapeutics was highly effective in the aggressive MMTV-neu mouse tumor model