Background: Breast cancer (BC) is the most common cancer in women worldwide and there is a need for more targeted BC prevention strategies. The selective estrogen receptor modulator tamoxifen (TAM) has been shown to reduce the risk of estrogen receptor (ER) positive but not ER negative BC. Furthermore, TAM does not reduce BC mortality but can induce troublesome side effects. Predictive biomarkers for preventive TAM therapy are required. Methods: A clinical trial was set up in which premenopausal women at increased risk of BC, due to start taking TAM, had a biopsy of one breast in the luteal phase of the menstrual cycle and then a biopsy of the contralateral breast after 3 months of TAM treatment. Biopsy samples were subjected to multiple analytical techniques including immunohistochemistry, RNA sequencing (RNAseq) and Laser Capture Microdissection coupled to Mass Spectrometry (LCM-MS). The principal hypothesis was that examining interpatient variation in response could lead to the development of predictive biomarkers of TAM prevention. We also sought to develop in vitro culture of normal breast tissue that could help to test novel preventive approaches. Results: 12 weeks of TAM treatment significantly reduced the average epithelial proliferation, normal breast acinar area and estrogen and progesterone receptor expression levels in 10 paired samples. However, there was clear interindividual variation in response with some participants showing increases in certain parameters. TAM induced changes in gene expression (RNAseq) in particular in a luminal hormone receptor positive cell signature identified two broad groups of response (RG1 and RG2). RG2 was characterized by an increase in gene expression in a set of estrogen and androgen responsive genes. Similar findings were observed in a subset of these samples subjected to LCM-MS. In vitro culture of intact breast tissue without a supporting matrix revealed massive disruption of gene expression by RNAseq, not previously reported. Encouraging results were obtained with hydrogel culture but more optimization work is required. Conclusions: Alterations in ER and/or AR signaling in response to TAM may define mechanisms of normal tissue resistance to TAM. Further work is ongoing to increase the sample size and to analyse blood from all participants to determine whether circulating biomarkers that correlate with the changes in breast tissue can be identified. Personalised BC prevention may be one step closer.
- Breast cancer, Mammographic Density, Tamoxifen, Proliferation
Investigation of Preventive Tamoxifen Resistance Mechanisms in the Normal Breast
Alghamdi, S. (Author). 31 Dec 2022
Student thesis: Phd