Estrogen receptors (ER) and progesterone receptors (PR) are clinical markers that predict breast cancer responsiveness to endocrine therapies. Additionally, PRs alone are independent markers of good prognosis. ER and PR are always co-expressed in normal and malignant cells, and cross talk between estrogen and progesterone signaling is well known. PRs exist as two forms called PR-A and PR-B. The two PRs are present in equal amounts in normal cells, but the A:B ratio is strongly dysregulated in breast cancers. This is important because PR-A and PR-B control different sets of genes and have different functions. We have established solid, estrogen-dependent, tumors in nude mice from 4 human breast cancer cell lines that express: both PRs, neither PR, PR-A or PR-B. The cells are otherwise identical. Invariably, PR-A containing tumors are half the size of PR-B containing tumors. Why? I now plan to study the mechanisms by which the two PRs differentially influence estrogen-mediated signaling in breast cancers. I hypothesize that PR-A and PR-B have different effects on estrogen,target genes. As a result, the growth promoting and morphologic effects of estrogens are critically influenced by the type of PR present in a tumor.
Aim 1. To define estrogen-regulated genes involved in human breast tumor growth, and their differential modulation by PR-A vs. PR-B. Estrogen dependent tumors will be grown in mice from cells expressing no PR, or each PR isoform. Expression profiling studies will define: i. estrogen (+E) regulated genes in the absence of PRs; ii. effects of unliganded PR-A or PR-B on +E gene expression; iii. effects of PR occupancy by medroxyprogesterone acetate (MPA) on +E gene expression.
Aim 2. To define mechanisms by which PR-A and PR-B differentially modulate the phenotype of estrogen-dependent tumors, focusing on the estrogen-inhibitory properties of PR-A. These studies use cell lines with stably integrated PRs or cells in which PRs can be switched """"""""on"""""""" and """"""""off"""""""". I will define the morphology, motility and invasiveness properties of the cells treated with +E, and as modified by each PR with and without MPA. I will analyze specifically, the regulation of four known +E regulated genes involved in breast cancer and ask how unliganded or liganded PRs influence this regulation by +E. Together, these experiments will define how PRs influence +E signaling in breast cancers.
| Harvell, Djuana M E; Richer, Jennifer K; Singh, Meenakshi et al. (2008) Estrogen regulated gene expression in response to neoadjuvant endocrine therapy of breast cancers: tamoxifen agonist effects dominate in the presence of an aromatase inhibitor. Breast Cancer Res Treat 112:489-501 |
| Harvell, Djuana M E; Spoelstra, Nicole S; Singh, Meenakshi et al. (2008) Molecular signatures of neoadjuvant endocrine therapy for breast cancer: characteristics of response or intrinsic resistance. Breast Cancer Res Treat 112:475-88 |
| Harvell, Djuana M E; Richer, Jennifer K; Allred, D Craig et al. (2006) Estradiol regulates different genes in human breast tumor xenografts compared with the identical cells in culture. Endocrinology 147:700-13 |
