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Estrogen receptor-positive mammary tumorigenesis in TGFalpha transgenic mice progresses with progesterone receptor
T A Rose-Hellekant1, M D Schroeder, J L Brockman
1Department of Pathobiological Sciences, University of Wisconsin-Madison, Madison, WI, USA. trosehel@d.umn.edu
Abstract:
We characterized the novel NRL-transforming growth factor alpha (NRL-TGFalpha) transgenic mouse model in which growth factor - steroid receptor interactions were explored. The NRL promoter directs transgene expression to mammary ductal and alveolar cells and is nonresponsive to estrogen manipulations in vitro and in vivo. NRL-TGFalpha mice acquire proliferative hyperplasias as well as cystic and solid tumors. Quantitative transcript analysis revealed a progressive decrease in estrogen receptor alpha (ER) and progesterone receptor (PR) mRNA levels with tumorigenesis. However, ER protein was evident in all lesion types and in surrounding stromal cells using immunohistochemistry. PR protein was identified in normal epithelial cells and in very few cells of small epithelial hyperplasias, but never in stromal or tumor cells. Prophylactic ovariectomy significantly delayed tumor development and decreased incidence. Finally, while heterozygous (+/-) p53 mice did not acquire mammary lesions, p53+/- mice carrying the NRL-TGFalpha transgene developed ER negative/PR negative undifferentiated carcinomas. These data demonstrate that unregulated TGFalpha expression in the mammary gland leads to oncogenesis that is dependent on ovarian steroids early in tumorigenesis. Resulting tumors resemble a clinical phenotype of ER+/PR-, and when combined with a heterozygous p53 genotype, ER-/PR-.
Insights
Unregulated transforming growth factor alpha (TGFalpha) in mammary glands drives tumor growth, dependent on ovarian steroids. Tumor development is influenced by estrogen receptor (ER) and progesterone receptor (PR) levels and p53 status.
Area of Science:
- Mammary gland biology
- Cancer research
- Endocrinology
Background:
- Transforming growth factor alpha (TGFalpha) plays a role in mammary gland development and tumorigenesis.
- Steroid hormone receptors, estrogen receptor alpha (ER) and progesterone receptor (PR), are critical in normal mammary gland function and breast cancer.
Purpose of the Study:
- To characterize a novel NRL-TGFalpha transgenic mouse model to explore growth factor-steroid receptor interactions in mammary tumorigenesis.
- To investigate the role of ER and PR in TGFalpha-induced mammary tumors.
- To assess the impact of ovarian steroids and p53 status on tumor development.
Main Methods:
- Generation of NRL-TGFalpha transgenic mice.
- Mammary tissue analysis using quantitative transcript analysis and immunohistochemistry.
- Prophylactic ovariectomy in mice.
- Genotyping for p53 heterozygosity.
Main Results:
- NRL-TGFalpha mice developed mammary hyperplasias and tumors.
- Tumorigenesis correlated with decreased ER and PR mRNA, but ER protein was present in lesions and stroma.
- PR protein was detected in normal and hyperplastic cells but not in tumors or stroma.
- Ovariectomy delayed tumor onset and reduced incidence.
- p53+/- NRL-TGFalpha mice developed ER-/PR- undifferentiated carcinomas.
Conclusions:
- Unregulated TGFalpha expression drives mammary oncogenesis dependent on ovarian steroids early in the process.
- TGFalpha-induced tumors exhibit phenotypes resembling ER+/PR- and ER-/PR- human breast cancers.
- The model provides insights into growth factor and steroid receptor interplay in mammary cancer.
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