Antiestrogens are used to treat estrogen receptor positive (ER+) breast tumors that constitute 70% of all breast cancer cases. Unfortunately, acquired resistance to antiestrogen therapy remains a critical clinical obstacle. Here we show that human breast cancer cells and rat mammary tumors that have acquired resistance to antiestrogens express increased levels of MYC, a major regulator of both ...

The underlying mechanisms leading to antiestrogen resistance in estrogen-receptor α (ER)-positive breast cancer is still poorly understood. The aim of this study was therefore to identify biomarkers and novel treatments for antiestrogen resistant breast cancer. We performed a kinase inhibitor screen on antiestrogen responsive T47D breast cancer cells and T47D-derived tamoxifen and fulvestrant r...

We have investigated the effects of estrogens and antiestrogens on cellular DNA-dependent DNA polymerase activity in human breast cancer, using as a model the MCF-7 human breast cancer cell line which contains estrogen receptor. 17 beta-Estradiol had little if any effect on cytosol DNA polymerase activity or growth (total DNA per flask) of MCF-7 cells. Incubation of the cells for 4 to 6 days wi...

Purpose: Estrogen receptor-a (ERa)-targeted therapies including tamoxifen (TAM) or Faslodex (ICI) are used to treat ERþ breast cancers. Up to 50% of tumors will acquire resistance to these interventions. Autophagy has been implicated as a major driver of antiestrogen resistance. We have explored the ability of chloroquine (CQ), which inhibits autophagy, to affect antiestrogen responsiveness. Ex...

PURPOSE Estrogen receptor-α (ERα)-targeted therapies including tamoxifen (TAM) or Faslodex (ICI) are used to treat ER(+) breast cancers. Up to 50% of tumors will acquire resistance to these interventions. Autophagy has been implicated as a major driver of antiestrogen resistance. We have explored the ability of hydroxychloroquine (HCQ), which inhibits autophagy, to affect antiestrogen responsiv...

In search of novel mechanisms leading to the development of antiestrogen-resistance in human breast tumors, we analyzed differences in the gene and protein expression pattern of the human breast carcinoma cell line T47D and its derivative T47D-r, which is resistant toward the pure antiestrogen ZM 182780 (Faslodex trade mark, fulvestrant). Affymetrix DNA chip hybridizations on the commercially a...

PR1 cells are a prolactin (PRL)-secreting cell line derived from a pituitary lactotroph tumor found in 17beta-estradiol-treated Fischer 344 rats. We examined the effect of estrogen on cell proliferation and PRL synthesis under various culture conditions. Estrogen, at extremely low concentrations, induces cell proliferation in this cell line, whereas antiestrogen inhibits proliferation. Interest...

Cyclin E2, but not cyclin E1, is included in several gene signatures that predict disease progression in either tamoxifen-resistant or metastatic breast cancer. We therefore examined the role of cyclin E2 in antiestrogen resistance in vitro and its potential for therapeutic targeting through cyclin-dependent kinase (CDK) inhibition. High expression of CCNE2, but not CCNE1, was characteristic of...

In estrogen receptor–positive (ERþ) breast cancer cells, BCL2 overexpression contributes to antiestrogen resistance. Direct targeting of the antiapoptotic BCL2 members with GX15-070 (obatoclax), a BH3-mimetic currently in clinical development, is an attractive strategy to overcome antiestrogen resistance in some breast cancers. Recently, GX15-070 has been shown to induce both apoptosis and auto...