Breast Cancer Research
Breast cancer is the most common cancer diagnosed in women, making up 23% of all cancers in women, with 1.38 million new cases worldwide annually, making up 10.9% of all cancer (men and women), ranking it second only to lung cancer. Breast Cancer is the most frequent cause of cancer death in women worldwide, with 460K deaths per annum. In developed regions, breast cancer mortality ranks it equal first with lung cancer deaths in women (http://globocan.iarc.fr). Furthermore, breast cancer incidence in the West has risen over the last century and continues to rise. In Europe, breast cancer incidence has risen 72% between 1975-1977 and 2008-2010 (http://www.cancerresearchuk.org/cancer-info/cancerstats/types/breast/incidence/). Breast cancer incidence is also rising rapidly in many other parts of the world. For example, in 2008 170K new cases were diagnosed in China, but some studies estimate that this number may reach 2.5M cases per annum by 2021 (Linos et al 2008 JNCI 100: 1352-1360), a 15-fold increase in little over a decade. These enormous increases in breast cancer incidence world-wide, often accompanied by lifestyle changes known to influence breast cancer development, mean that breast cancer is an important global health issue.
In most cases, breast cancer is estrogen dependent. Estrogen acts by binding to the estrogen receptor (ER), a transcription regulatory protein that acts by altering gene expression in breast cancer cells. Endocrine therapies are aimed at inhibiting ER activity by competing with estrogen for binding to ER in the case of anti-estrogens such as tamoxifen, or prevent ER activation by inhibiting estrogen biosynthesis (aromatase inhibitors). The use of these endocrine agents has contributed to a significant reduction in breast cancer mortality in the Western World over the last 10-15 years. Moreover, recent clinical studies have demonstrated that these endocrine agents are also efficacious for breast cancer prevention in women at high risk of developing breast cancer.
A major clinical problem, however, is that a substantial proportion of patients presenting with localized disease, and all of the patients with metastatic disease, become resistant to endocrine therapies. In most cases, ER is present in resistant tumours, and in many cases continues to regulate tumour growth, indicating that changes that allow ER activation in the absence of hormone can occur in the development of endocrine resistance.
The purpose of our research is to better understand the molecular mechanisms of ER action through the use of proteomic, transcriptomic, genomic and epigenomic studies using cell line models of breast cancer and in patient material. Particular highlights include:
- the identification of ER phosphorylation at specific sites is important for regulating its activity, and have developed specific antibodies for the detection of ER phosphorylated at specific residue for evaluation of the clinical significance of these phosphorylation events. These studies have led to the development of new drugs targeting ER phosphorylation,
- we have also identified ER-associated proteins that facilitate regulation of gene expression by ER. The focus of current research is the determination of the importance of these and other proteins that modulate ER activity, in endocrine response and resistance in breast cancer. Of special note is work in which we have identified important links between ER signalling and DNA damage recognition and repair pathways that are often deregulated in cancer.
- we are also investigating the importance of ER-regulated genes identified through transcriptomic approaches to determine their clinical and mechanistic importance for breast cancer progression, response and resistance to therapies.
Prostate Cancer Research
Prostate cancer is a major disease affecting men. In many cases, prostate cancer growth is stimulated by androgens, acting through the androgen receptor (AR) transcription factor, a protein similar to ER. We have been carrying out gene expression profiling to identify androgen-responsive genes which mediate the growth stimulatory effects of androgens in prostate cancer cells, in order to identify novel diagnostic and predictive markers, and to develop new therapies for the treatment of prostate cancer. This work has identified several potential biomarkers for monitoring prostate cancer progression and response to therapies, and potential therapeutic targets that are being developed through a drug discovery program.
Some of our recent findings have led to the establishment of drug discovery programs, which are being used to develop new therapies for the treatment of endocrine resistant breast cancer through the Imperial College Cancer Drug Design and Development Group (http://www1.imperial.ac.uk/medicine/about/institutes/drugdiscoverycentre/cd3/).
et al., 2020, Activating transcription factor-2 (ATF2) is a key determinant of resistance to endocrine treatment in an in vitro model of breast cancer, Breast Cancer Research, Vol:22
Sava GP, Ali S, 2020, Developing themes in targeted therapies for hormone receptor–positive breast cancer, Current Opinion in Endocrine and Metabolic Research, Vol:15, ISSN:2451-9650, Pages:15-23
et al., 2020, Induction of APOBEC3B expression by chemotherapy drugs is mediated by DNA-PK directed activation of NF-κB, Oncogene, ISSN:0950-9232
et al., 2020, Genome-wide alterations of uracil distribution patterns in human DNA upon chemotherapeutic treatments, Elife, Vol:9, ISSN:2050-084X, Pages:1-37
et al., 2023, Control of gene expression using a complex of an oligonucleotide and a regulatory peptide, US2005136040