Prevention of tumorigenesis in p53-null mammary epithelium by rexinoid bexarotene, tyrosine kinase inhibitor gefitinib, and celecoxib

Abstract

The chemopreventive effects of three agents, rexinoid bexarotene, tyrosine kinase inhibitor gefitinib, and celecoxib, were tested on mammary tumor development arising in p53-null mammary epithelium. The rexinoid bexarotene was the most efficacious inhibitor as it reduced mammary tumor development by 75% in virgin mice and significantly delayed mean tumor development by 98 days in hormone-stimulated mice. The tyrosine kinase inhibitor gefitinib reduced mammary tumor incidence by 50% in virgin mice but did not significantly delay mean tumor latency in hormone-stimulated mice. Celecoxib did not reduce tumor incidence or mean tumor latency in either of the two models. The high doses of the rexinoid and the tyrosine kinase inhibitor did not affect the progression of tumors arising from the premalignant mammary outgrowth line, PN8a. A comparison of these agents with tamoxifen shows the superiority of tamoxifen in preventing tumor development in p53-null mammary cells. Similarly, a comparison of the results of the p53 model with other transgenic models in their response to the chemopreventive agents showed that mammary tumors arising from different oncogenic events will respond differently to the different agents.

Figure 1

The effect of gefitinib on the tumor-producing capabilities of p53 null mammary epithelium transplanted into virgin or pituitary-isograft bearing mice. Gefitinib delayed tumorigenesis in virgin mice () compared to sham controls (). Gefitinib did not have any effect on tumorigenesis in hormone-stimulated hosts.

Figure 2

The effect of gefitinib on mammary cell proliferation as measured by BrdU incorporation. There were no differences in cell proliferation in any of the five groups of mice. Number in parentheses represents individual number of glands evaluated for BrdU. gef = gefitinib; lo = low; hi = high; pit = pituitary-isograft.

Figure 3

The effect of bexarotene on the tumor-producing capabilities of p53 null mammary epithelium in pituitary-isograft bearing mice. Bexarotene significantly delayed tumorigenesis at the high dose () but not at the low does () compared to control mice ().

Figure 4

The effect of bexarotene on the tumor-producing capabilities of p53 null mammary epithelium in virgin mice. The high dose of bexarotene () but not the low does () delayed tumorigenesis compared to control mice ().

Figure 5

The effect of bexarotene and celecoxib on mammary cell proliferation as measured by BrdU incorporation. Asterisk marks values that are significantly different (P < 0.05). Bexarotene, but not celecoxib, altered BrdU incorporation. Numbers in parentheses represent number of individual glands evaluated for BrdU incorporation. c = control, p = pituitary, l = low dose; h = high dose; b = bexarotene; c = celecoxib.

Figure 6

The effect of celecoxib on the tumor-producing capabilities of p53 null mammary epithelium transplanted into virgin or pituitary-isograft bearing mice. There was no significant effect of celecoxib on tumorigenesis in either the virgin or pituitary-isograft bearing mice.