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Hormone-induced protection of mammary tumorigenesis in genetically engineered mouse models.

Rajkumar L, Kittrell FS, Guzman RC, Brown PH, Nandi S, Medina D - Breast Cancer Res. (2007)

Bottom Line: In the p53- mammary transplant model, a 2-week exposure to estrogen and progesterone during the immediate post-pubertal stage (2 to 4 weeks after transplantation) of mammary development decreased mammary tumorigenesis by 70 to 88%.One possible mechanism for the decrease in mammary tumorigenesis may be an altered proliferation activity as the bromodeoxyuridine labeling index was decreased by 85% in the mammary glands of hormone-treated mice.Because these experiments were performed in model systems that mimic many essential elements of human breast cancer, the results strengthen the rationale for translating this prevention strategy to humans at high risk for developing breast cancer.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pathology, Texas Tech University Health Sciences Center, 4800 Alberta Avenue, El Paso, TX 79905, USA.

ABSTRACT

Introduction: The experiments reported here address the question of whether a short-term hormone treatment can prevent mammary tumorigenesis in two different genetically engineered mouse models.

Methods: Two mouse models, the p53- mammary epithelial transplant and the c-neu mouse, were exposed to estrogen and progesterone for 2 and 3 weeks, respectively, and followed for development of mammary tumors.

Results: In the p53- mammary transplant model, a 2-week exposure to estrogen and progesterone during the immediate post-pubertal stage (2 to 4 weeks after transplantation) of mammary development decreased mammary tumorigenesis by 70 to 88%. At 45 weeks after transplantation, analysis of whole mounts of the mammary outgrowths demonstrated the presence of premalignant hyperplasias in both control and hormone-treated glands, indicating that the hormone treatment strongly affects the rate of premalignant progression. One possible mechanism for the decrease in mammary tumorigenesis may be an altered proliferation activity as the bromodeoxyuridine labeling index was decreased by 85% in the mammary glands of hormone-treated mice. The same short-term exposure administered to mature mice at a time of premalignant development also decreased mammary tumorigenesis by 60%. A role for stroma and/or systemic mediated changes induced by the short-term hormone (estrogen/progesterone) treatment was demonstrated by an experiment in which the p53- mammary epithelial cells were transplanted into the cleared mammary fat pads of previously treated mice. In such mice, the tumor-producing capabilities of the mammary cells were also decreased by 60% compared with the same cells transplanted into unexposed mice. In the second set of experiments using the activated Her-2/neu transgenic mouse model, short-term estradiol or estradiol plus progesterone treatment decreased mammary tumor incidence by 67% and 63%, and tumor multiplicity by 91% and 88%, respectively. The growth rate of tumors arising in the hormone-treated activated Her-2/neu mice was significantly lower than tumors arising in non-hormone treated mice.

Conclusion: Because these experiments were performed in model systems that mimic many essential elements of human breast cancer, the results strengthen the rationale for translating this prevention strategy to humans at high risk for developing breast cancer.

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The effect of duration of hormone exposure on tumorigenesis in p53- mammary epithelial transplants. The effect of hormone exposure was compared with that of a hormone receptor antagonist, tamoxifen. Mice treated with estradiol and progesterone, either early or late, or treated with tamoxifen, had a significant decrease in tumor incidence (p < 0.05). Filled circles and solid line, control; filled circles and dotted line, early hormone exposure; inverted triangles and broken line, late hormone exposure; upright triangle, tamoxifen. The flow diagram illustrates the experimental treatment plan.
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Figure 3: The effect of duration of hormone exposure on tumorigenesis in p53- mammary epithelial transplants. The effect of hormone exposure was compared with that of a hormone receptor antagonist, tamoxifen. Mice treated with estradiol and progesterone, either early or late, or treated with tamoxifen, had a significant decrease in tumor incidence (p < 0.05). Filled circles and solid line, control; filled circles and dotted line, early hormone exposure; inverted triangles and broken line, late hormone exposure; upright triangle, tamoxifen. The flow diagram illustrates the experimental treatment plan.

Mentions: The tumorigenic response of the mammary epithelium exposed to estrogen and progesterone combination at 23 to 25 weeks after transplantation is shown in Figure 3 and Table 1. In the control transplants, 10/20 (50%) produced tumors by 48 weeks after transplantation, with an initial tumor latency of 24 weeks. In the transplants exposed to hormone combination when they were actively filling the fat pad, the tumor incidence was 3/20 (15%), with an initial tumor latency of 44 weeks. In contrast, the transplants exposed to the hormone combination much later after transplantation had an initial tumor latency equivalent to the controls, but the final tumor incidence (4/20; 20%) was not significantly different (p > 0.05) from that in the group exposed to hormones early after transplantation. The transplants exposed to tamoxifen for only 3 months did not develop any tumors after 50 weeks. This experiment demonstrates that a short-term treatment administered at either the actively proliferating or the steady-state stage of mammary development can delay tumorigenesis.


Hormone-induced protection of mammary tumorigenesis in genetically engineered mouse models.

Rajkumar L, Kittrell FS, Guzman RC, Brown PH, Nandi S, Medina D - Breast Cancer Res. (2007)

The effect of duration of hormone exposure on tumorigenesis in p53- mammary epithelial transplants. The effect of hormone exposure was compared with that of a hormone receptor antagonist, tamoxifen. Mice treated with estradiol and progesterone, either early or late, or treated with tamoxifen, had a significant decrease in tumor incidence (p < 0.05). Filled circles and solid line, control; filled circles and dotted line, early hormone exposure; inverted triangles and broken line, late hormone exposure; upright triangle, tamoxifen. The flow diagram illustrates the experimental treatment plan.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC1851398&req=5

Figure 3: The effect of duration of hormone exposure on tumorigenesis in p53- mammary epithelial transplants. The effect of hormone exposure was compared with that of a hormone receptor antagonist, tamoxifen. Mice treated with estradiol and progesterone, either early or late, or treated with tamoxifen, had a significant decrease in tumor incidence (p < 0.05). Filled circles and solid line, control; filled circles and dotted line, early hormone exposure; inverted triangles and broken line, late hormone exposure; upright triangle, tamoxifen. The flow diagram illustrates the experimental treatment plan.
Mentions: The tumorigenic response of the mammary epithelium exposed to estrogen and progesterone combination at 23 to 25 weeks after transplantation is shown in Figure 3 and Table 1. In the control transplants, 10/20 (50%) produced tumors by 48 weeks after transplantation, with an initial tumor latency of 24 weeks. In the transplants exposed to hormone combination when they were actively filling the fat pad, the tumor incidence was 3/20 (15%), with an initial tumor latency of 44 weeks. In contrast, the transplants exposed to the hormone combination much later after transplantation had an initial tumor latency equivalent to the controls, but the final tumor incidence (4/20; 20%) was not significantly different (p > 0.05) from that in the group exposed to hormones early after transplantation. The transplants exposed to tamoxifen for only 3 months did not develop any tumors after 50 weeks. This experiment demonstrates that a short-term treatment administered at either the actively proliferating or the steady-state stage of mammary development can delay tumorigenesis.

Bottom Line: In the p53- mammary transplant model, a 2-week exposure to estrogen and progesterone during the immediate post-pubertal stage (2 to 4 weeks after transplantation) of mammary development decreased mammary tumorigenesis by 70 to 88%.One possible mechanism for the decrease in mammary tumorigenesis may be an altered proliferation activity as the bromodeoxyuridine labeling index was decreased by 85% in the mammary glands of hormone-treated mice.Because these experiments were performed in model systems that mimic many essential elements of human breast cancer, the results strengthen the rationale for translating this prevention strategy to humans at high risk for developing breast cancer.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pathology, Texas Tech University Health Sciences Center, 4800 Alberta Avenue, El Paso, TX 79905, USA.

ABSTRACT

Introduction: The experiments reported here address the question of whether a short-term hormone treatment can prevent mammary tumorigenesis in two different genetically engineered mouse models.

Methods: Two mouse models, the p53- mammary epithelial transplant and the c-neu mouse, were exposed to estrogen and progesterone for 2 and 3 weeks, respectively, and followed for development of mammary tumors.

Results: In the p53- mammary transplant model, a 2-week exposure to estrogen and progesterone during the immediate post-pubertal stage (2 to 4 weeks after transplantation) of mammary development decreased mammary tumorigenesis by 70 to 88%. At 45 weeks after transplantation, analysis of whole mounts of the mammary outgrowths demonstrated the presence of premalignant hyperplasias in both control and hormone-treated glands, indicating that the hormone treatment strongly affects the rate of premalignant progression. One possible mechanism for the decrease in mammary tumorigenesis may be an altered proliferation activity as the bromodeoxyuridine labeling index was decreased by 85% in the mammary glands of hormone-treated mice. The same short-term exposure administered to mature mice at a time of premalignant development also decreased mammary tumorigenesis by 60%. A role for stroma and/or systemic mediated changes induced by the short-term hormone (estrogen/progesterone) treatment was demonstrated by an experiment in which the p53- mammary epithelial cells were transplanted into the cleared mammary fat pads of previously treated mice. In such mice, the tumor-producing capabilities of the mammary cells were also decreased by 60% compared with the same cells transplanted into unexposed mice. In the second set of experiments using the activated Her-2/neu transgenic mouse model, short-term estradiol or estradiol plus progesterone treatment decreased mammary tumor incidence by 67% and 63%, and tumor multiplicity by 91% and 88%, respectively. The growth rate of tumors arising in the hormone-treated activated Her-2/neu mice was significantly lower than tumors arising in non-hormone treated mice.

Conclusion: Because these experiments were performed in model systems that mimic many essential elements of human breast cancer, the results strengthen the rationale for translating this prevention strategy to humans at high risk for developing breast cancer.

Show MeSH
Related in: MedlinePlus