– Cathrin Brisken (PI)- Laboratory of breast carcinogenesis – PhD projects 1 – 2
Sex hormone signaling plays an important and complex role in the pathogenesis of breast cancer (BC), especially hormone receptor positive (HR+) BCs, which represent ³ 70% of all BCs. We hypothesize that estrogen receptor (ER), progesterone receptor (PR) and/or androgen receptor (AR) signaling pathways are deregulated early during breast carcinogenesis. More specifically, by studying the interplay between respective hormone signaling pathways, and their downstream target genes, in particular, inflammatory cytokines, we aim to uncover how these signaling networks can be exploited to block progression of pre-cancerous lesions in the breast. Two PhD students’ projects are available :
Project 1 – Effects of different progestins used in hormonal contraception and hormone replacement therapy on the breast epithelium.
Hypothesis: Androgenic and anti-androgenic activities determine the ability of different progestins to induce inflammatory cytokines and cell proliferation in the human breast epithelium.
Background and Significance: Reproductive hormones control normal breast development and impact on breast carcinogenesis[1]. In particular, recurrent activation of PR signaling as it occurs during the luteal phase of the menstrual cycle increases BC risk[2]. We and others have shown that progesterone induces cell proliferation by a paracrine mechanism involving the cytokine RANKL[3]. Through hormonal contraception and hormone replacement therapy women are exposed to synthetic PR agonists, progestins, and these exposures increase their BC (BC) risk. Progestins differ in chemical structure and affinities for other nuclear receptors, in particular AR. Little is known about their actions on the breast because we lacked model systems to study these. The Brisken Laboratory has developed ex vivo[4] and in vivo models[5] to study hormone action in the human breast epithelium in physiologically relevant conditions. Determining the biological activities of different progestins will help to develop more informed choices in hormonal contraception and replacement therapy.
Objectives: (1) Use physiologically relevant ex vivo and in vivo models to study the effects of progestins on the breast epithelium; (2) Determine how progestins with different androgenic properties affect cell proliferation in the human breast epithelium; (3) Determine how different progestins affect the expression of inflammatory cytokines; (4) Test whether pharmacological inhibition of AR signaling abrogates progestin-induced cell proliferation and cytokine induction.
Project 2 – Personalized endocrine prevention of Breast Cancer progression.
Hypothesis: ER, PR and AR signaling are deregulated during breast carcinogenesis in different ways in individual patients and provide targets for personalized prevention of disease progression.
Background and Significance: Reproductive hormones, estrogens, progesterone, and androgens impinge on breast carcinogenesis in complex poorly understood ways. The Brisken lab developed intraductal xenograft models for hormone receptor positive Breast Cancer with unprecedented take rates that allow study of disease progression from precursor to invasive and metastatic lesions in a normal endocrine milieu[1]. We have preliminary evidence that different ER+ tumors respond differentially to individual hormones and combinations thereof.
Objectives: (1) ESR2 will exploit intraductal PDXs from different patients to determine the importance of ER vs PR and AR signaling in ER+ BCs using genetic (shRNA) and pharmacological approaches (HR modulators); (2) ESR2 will establish global gene expression profiles of intraductal xenografts from obj. 1 by RNAseq; (3) ESR2 will characterize signatures for response to inhibition of different hormone receptors; (4) ESR2 will use the gene expression signatures to identify biomarkers that predict patient response to different HR modulators.
Related readings
[1] Brisken, C. & O’Malley, B. Hormone action in the mammary gland. Cold Spring Harb Perspect Biol 2, a003178 (2010).
[2] Brisken, C. Progesterone signalling in BC: a neglected hormone coming into the limelight. Nat Rev Cancer 13, 385-396 (2013).
[3] Beleut, M. et al. Two distinct mechanisms underlie progesterone-induced proliferation in the mammary gland. Proc Natl Acad Sci USA 107, 2989-2994 (2010).
[4] Tanos, T. et al. Progesterone/RANKL is a major regulatory axis in the human breast. Sci Transl Med 5, 182ra155 (2013).
[5] Sflomos, G. et al. A Preclinical Model for ERalpha-Positive BC Points to the Epithelial Microenvironment as Determinant of Luminal Phenotype and Hormone Response. Cancer Cell 29, 407-422 (2016).