Professor Eric Lam:
Breast cancer is the most common cancer in women, with 1 in 8 of all British and American women developing breast cancer in their lifetimes and is the second most prevalent cause of cancer death in the western hemisphere. The expression of oestrogen receptor alpha (ERα) is a good prognostic factor in breast cancer as about two-thirds of these ERα-positive (ER+) patients respond to hormone therapy – i.e. treatment with anti-estrogens such as tamoxifen, ICI 182,780 (fulvestrant), or aromatase inhibitors. However, approximate half of the patients that initially respond to hormonal therapy develop resistance and relapse, following long-term treatment. This pattern of initial response, resistance and relapse is also seen following chemotherapy treatment. In fact, chemotherapy is used in more than half of all people diagnosed with cancer. Chemotherapy is used commonly to treat breast cancer patients, but most treatments eventually fail also because of the development of resistance. Understanding and overcoming resistance to current therapies is the key to developing new cancer treatments and improving patient outcomes and increasing survival.
We are a group of 12-18 researchers, studying the signalling mechanisms in breast cancer, as well as the components involved in tumorigenesis and cancer drug resistance. In particular, we are interested in the FOXO and FOXM1 subgroups of forkhead superfamily of transcription factors that integrate the proliferative and cell survival signals from the PI3-kinase cascade with the gene expression machinery. FOXO and FOXM1 proteins play a crucial part in normal G1-S, G2 and M cell cycle phase transitions as well as apoptosis, angiogenesis, senescence, development and DNA damage repair. By elucidating the signalling mechanisms of these transcription factors, we hope to better understand their roles during cancer progression and drug resistance.
Our work focuses on two transcription factor subfamilies: FOXO transcription factors, function downstream of the PI3K-PTEN-AKT (PKB) signalling cascade and are essential for cell proliferation, differentiation, DNA damage repair, and apoptosis; FOXM1 is another forkhead transcription factor implicated in cell proliferation and survival. Deregulation of FOXM1 expression has been observed in various types of cancer, including tumours of the liver, breast, lung, prostate, cervix and uterus, colon, pancreas, and brain. FOXM1 is involved in initial stages of tumorigenesis and one of first genes to become overactivated during cancer initiation. In addition to its role in tumorigenesis, FOXM1 also acts as a cellular mediator for drug sensitivity and resistance. Our previous work has demonstrated a role for FOXM1 in DNA damage repair in cisplatin sensitive and resistant cells.
Inactivation of FOXO or overexpression of FOXM1 is associated with tumorigenesis and cancer progression. In addition, the cytostatic and cytotoxic effects of a diverse spectrum of anti-cancer drugs, such as paclitaxel, doxorubicin, lapatinib, gefitinib, imatinib, and cisplatin, are mediated through the activation of FOXO3a and/or the inhibition of its target FOXM1. FOXM1 and FOXO activity is heavily regulated by post-transcriptional modifications. We also have many years of experience studying the cell cycle, cell death signals, the PI-3 kinase signalling pathway and transcription control.
Our current work focuses on the role and regulation of FOXO, FOXM1 and their co-factors as well as other forkhead transcription factors in cancer development and drug resistance. We have extensive collaborations with biological as well as non-biological scientists, including clinicians, chemists and physicists etc. within and outside the College. Our post-doctoral fellows and PhD students are involved in projects related to imaging, nanotechnology, drug discovery and development.
Khongkow P, Karunarathna U, Khongkow M, et al., 2013, FOXM1 targets NBS1 to regulate DNA damage-induced senescence and epirubicin resistance., Oncogene DOI Author Web Link
van Boxtel R, Gomez-Puerto C, Mokry M, et al., 2013, FOXP1 acts through a negative feedback loop to suppress FOXO-induced apoptosis., Cell Death Differ, Vol:20, 1350-9047, Pages:- DOI Author Web Link
Lin A, Yao J, Zhuang L, et al., 2013, The FoxO-BNIP3 axis exerts a unique regulation of mTORC1 and cell survival under energy stress., Oncogene, 0950-9232 DOI Author Web Link
Lam EW, Brosens JJ, Gomes AR, et al., 2013, Forkhead box proteins: tuning forks for transcriptional harmony., Nat Rev Cancer, Vol:13, 1474-175X, Pages:482-495 DOI Author Web Link
Gomes AR, Zhao F, Lam EW, 2013, Role and regulation of the forkhead transcription factors FOXO3a and FOXM1 in carcinogenesis and drug resistance., Ai Zheng, Vol:32, ISSN:1000-467X, Pages:- DOI Author Web Link
Brosens JJ, Lam EW, 2013, Progesterone and FOXO1 signaling: Harnessing cellular senescence for the treatment of ovarian cancer., Cell Cycle, Vol:12 Author Web Link
Khongkow M, Olmos Y, Gong C, et al., 2013, SIRT6 modulates paclitaxel and epirubicin resistance and survival in breast cancer., Carcinogenesis, Vol:34, 0143-3334, Pages: DOI Author Web Link
Coombes RC, Tat T, Miller ML, et al., 2013, An open-label study of lapatinib in women with HER-2-negative early breast cancer: the lapatinib pre-surgical study (LPS study)., Ann Oncol, Vol:24, 0923-7534, Pages:924-930 DOI Author Web Link
Zhao F, Lam EW, 2012, Role of the forkhead transcription factor FOXO-FOXM1 axis in cancer and drug resistance., Front Med, Vol:6, 2095-0217, Pages:376-380 DOI Author Web Link
Monteiro LJ, Khongkow P, Kongsema M, et al., 2013, The Forkhead Box M1 protein regulates BRIP1 expression and DNA damage repair in epirubicin treatment., Oncogene, Vol:32, 0950-9232, Pages:4634-4645 DOI Author Web Link
Siu MK, Wong ES, Kong DS, et al., 2013, Stem cell transcription factor NANOG controls cell migration and invasion via dysregulation of E-cadherin and FoxJ1 and contributes to adverse clinical outcome in ovarian cancers., Oncogene, Vol:32, 0950-9232, Pages:3500-3509 DOI Author Web Link