Date of Award

12-2006

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Legacy Department

Microbiology

Advisor

Chen, Wen

Abstract

Purpose: To study the role of prolactin (PRL) and its antagonist, G129R, in HER2/Neu tumorigenesis. Specifically, to investigate the interaction between the oncogene HER2 and the PRL receptor (PRLR) signaling pathways for designing effective combinational therapeutics for breast cancer.
Experimental Design: The combination effects of G129R and an anti-HER2 antibody, Herceptin, were tested against HER2-overexpressing human breast cancer cell lines, T-47D and BT-474, using cell based assays and xenografts established in athymic mice. Furthermore, four different bitransgenic mouse lines co-expressing the murine version of HER2 and PRL or G129R were generated. The mammary tumor incidence, characterization of mammary gland development, and alteration of the molecular biomarkers in the mammary glands were investigated in these transgenic mice.
Results: It was demonstrated that PRL was able to activate HER2 in human breast cancer cells and the addition of G129R competitively inhibited the stimulatory effect of hPRL. More importantly, G129R has synergistic/additive effects when used in combination with Herceptin in inhibiting HER2 activation. Results further demonstrate that Herceptin and G129R displayed a synergistic inhibitory effect on MAPK phosphorylation. Most importantly, the combinational treatment of Herceptin and G129R significantly inhibited the growth of xenografts in athymic mice.
In the bitransgenic mouse study, it was found that co-expression of G129R in MMTV-neu female mice had little effect on overall HER2 tumor incidence due to the low expression levels of G129R. Surprisingly, co-expression of low levels of PRL in MMTV-neu female mice demonstrated a drastic reduction in tumor incidence in both hPRL/neu bitransgenic lines. Suppressed expression of HER2, which lead to lower levels of MAPK activities and cyclin D1 expression were strong indications or evidence that support the significant change in the tumor incidence in these bitransgenic mice.
Conclusions: PRL possesses a dual role in HER2/neu tumorigenesis: as a tumor promoter in transformed cells and as a tumor suppressor when expressed early before tumor formation. To improve the outcome of breast cancer therapy, especially for HER2 positive breast cancer, G129R may be used together with Herceptin as a combinational therapy. On the other hand, data from the PRL bitransgenic mice suggests the possibility of using hPRL as a potential chemo-preventive agent in HER2/neu tumorigenesis.

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