Abstract LB-256: Estrogen and its receptors alpha and beta in different stages of breast carcinogenesis.
Authors: Huang Bo , Omoto Yoko , Iwase Hirotaka , Yamashita Hiroko , Toyama Tatsuya , Warner Margaret , Gustafsson Jan-Åke 
Published: August 2014

Excessive exposure to Estrogen has long been indicated to increase breast cancer risk. Although the anti-estrogen endocrine therapy by selective estrogen receptor modulator (SERM) is widely used to treat the ERα-positive breast cancers, there are several mysteries in the field: 1) Some ERα positive breast cancers do not respond to tamoxifen; 2) Some ERα negative breast cancers also respond to tamoxifen; 3) Strikingly, physiological estrogen can cause dramatic tumor regression of long-term tamoxifen-resistant ERα-positive breast cancer; 4) When ERα is overexpressed in genetically engineered mice, mammary tumors form but they do not progress to invasive cancer, which indicates that the activation of ERα alone does not fully explain the action of estrogen.

To uncover these mysteries, we focus on the following two main points: 1) Role of ERβ, the second estrogen receptor, which is the more abundant ER in the normal breast. Estradiol, the main type of estrogen, binds with ERα and ERβ with the similar affinity, but there are quite differences for some SERMs. 2) Differential function of two ERs in each stage of breast carcinogenesis. Breast cancer is a heterogeneous disease and also is a chronically developed disease, which occurs through a series of steps. The tumor cells in different development steps have distinct molecular profiles and clinical behaviors.

First we used a large set of well-documented surgical excised human ductal breast cancer samples and carefully examined the tumor histology and the expression of ERα and ERβ by IHC staining. Most of these samples contained normal areas as well as areas of hyperplasia, ductal carcinoma in situ (DCIS) and invasive ductal cancer (IDC). We compared ERα and ERβ expression in different cancer stages within each woman. Our results suggest that ERβ loss is an early event in breast carcinogenesis, ERα has dual role in cancer proliferation and invasion, and ERβ/ERα ratio seems to be one of the determinants for the breast cancer initiation and progression to malignancy.

Then we use inducible ERα transgenic mouse model to verify the findings in the human samples study. This ERα transgenic mouse develops DCIS, but not IDC. We use estradiol as well as several specific ligands for ERα and ERβ to treat this mouse and also generate a unique animal model by crossing ERα transgenic mouse with ERβ knockout mice to address the differential role of ERα and ERβ in breast cancer initiation and progression. The clinical application of our findings will be discussed.

Citation Format: Bo Huang, Yoko Omoto, Hirotaka Iwase, Hiroko Yamashita, Tatsuya Toyama, Margaret Warner, Jan-Åke Gustafsson. Estrogen and its receptors alpha and beta in different stages of breast carcinogenesis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-256. doi:10.1158/1538-7445.AM2013-LB-256