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Summary

About 70% of all breast cancers are positive for the estrogen receptor α (ERα). ERα is a transcription factor that is activated by the steroid hormone estrogen and then regulates the expression of a panel of genes. In a substantial proportion of breast cancers, active ERα supports excessive growth. This has led to the development of endocrine therapy, which attempts to prevent the activation of ERα with anti-estrogens such as tamoxifen or by blocking the production of estrogens with aromatase inhibitors. Although tamoxifen can be a very effective treatment, one third of the tumors eventually become resistant. While there are probably a vast number of mechanisms that can lead to this resistance, we have characterized one. This involves the activation of ERα by an alternate route. Moreover, mechanisms that we have found to affect the amounts of ERα are likely to have an impact as well. We therefore propose to study these factors as well as to apply state of the art high-throughput technologies to search more comprehensively for novel factors that regulate either the levels of ERα or its activities and to determine systematically whether they play a role in breast cancer and resistance to endocrine therapy.

Research focus

We propose to identify and to investigate cellular factors that affect estrogen signaling in a context that is relevant to breast cancer progression and treatment. Breast cancer now affects about one in eight women, and even though substantial progress has been made in early detection, treatment and management, it remains a serious and potentially fatal disease. Since the steroid hormone estrogen promotes the progression of a large proportion of breast cancers by activating the transcription factor "estrogen receptor α" (ERα), anti-estrogens such as tamoxifen are routinely prescribed as a specific adjuvant therapy. Although a relatively straightforward and simple therapy, some tumors are resistant from the outset or resistant variants often arise after years of treatment. Our project aims to achieve a better understanding of the cellular mechanisms that render breast cancer cells resistant to tamoxifen because of altered ERα function.
We have used two complementary biological systems to screen for factors that are required for ERα function.

Comprehensive genome-wide screens for factors required for estrogen-induced activity have been performed both with the budding yeast as a living test tube and by RNA interference in human cells. Some of these screens could be repeated with tamoxifen as well. As soon as we will have prioritized the preliminary hits from these screens, the most interesting subset will be further studied in human cells. The goals of these validation and follow-up experiments for individual candidate factors will be to characterize the molecular mechanisms, to determine their potential role for ERα-associated tamoxifen resistance with breast cancer cell lines and their expression in ERα-positive breast tumor biopsies, and the correlation between their expression and various clinical parameters (ERα and node status, recurrence, endocrine therapy resistance, ....).

In parallel with attempting to identify new/all factors, we will further explore miRNAs that we have found to regulate ERα levels and the components of an ERα complex that we have already found to be involved in tamoxifen resistance. We know that cAMP signaling can lead to tamoxifen-resistant ERα activity by allowing it to recruit the coregulator CARM1 once it has been phosphorylated by protein kinase A. We therefore want to complete our picture of the signaling pathways that lead to this activating phosphorylation and to examine the phosphorylation status of CARM1 in a panel of breast tumor biopsies to evaluate its potential mechanistic and diagnostic importance. Further studies on the other components of this unusual signaling complex, the molecular chaperone Hsp90 and the histone deacetylase 6 (HDAC6), will provide more detailed mechanistic insights and set the stage for fine-tuned diagnostics and for new therapeutic intervention schemes. We anticipate that our cell-based combinatorial drug "treatments" might eventually lead to new clinical trials.