Drug Resistance Lab

Lab Members

Academics

• Dr. Ernesto Yagüe

Researchers

• Dr. Yuan Zhou  yuan.zhou1@imperial.ac.uk
• Dr. Sabeena Rasul Rashied  s.rasul@imperial.ac.uk
• Yunhui Hu y.hu@imperial.ac.uk

• Giulia Cazzanelli giulia.cazzanelli11@imperial.ac.uk

Past Lab Members

• Caroline E. Adams (DIC)
• Ben Hitchinson (MRes Cancer Biology)
• Gina Tse (MRes Cancer Biology)
• Jose Costa Guerra (MRes Cancer Biology)
• Owen Bain (MRes Cancer Biology)
• Darren Zurawel (MSc Molecular Medicine)

Current projects

Molecular mechanisms of anthracyclins resistance in triple negative breast cancer

Approximately 10% of breast cancer cases belong to the triple negative (TN) category (estrogen and progesterone receptors-negative and ERBB2 (HER2/neu)-negative). This form of breast cancer is particularly aggressive and despite adjuvant chemotherapy with a combination of agents, including anthracyclines (doxorubicin or epirubicin), patients have a poor prognosis. Thus, there is a need to understand the mechanisms involved in TN chemotherapy resistance (relapse) with the ultimate goal of developing targeted therapies for this form of aggressive breast cancer.

CAL51 is a cell line derived from the pleural effusion of a 45-year old patient with invasive adenocarcinoma with extensive intraductal involvement. It is epithelial, tumorigenic in nude mice and clonogenic in soft agar, with a luminal phenotype negative for ER, PgR and ERBB2 and, contrary to other TN breast cancer cell lines, it has a normal diploid karyotype. CAL51 represents thus a good model to study TN breast cancer chemotherapy resistance.

We have generated a doxorubicin-resistant derivative of CAL51, hereby named CALDOX, by selection to 0.4 μM doxorubicin. CALDOX is microscopically indistinguishable from CAL51 but has a slower proliferation rate. Preliminary data indicates that CALDOX has a multidrug resistance phenotype, but the membrane pump P-glycoprotein, the most common effector of drug resistance, is not up-regulated.

Control of drug resistance by microRNAs in breast cancer cells

Micro RNAs (miRNAs) are a recently discovered class of small 21-23 nucleotide long non-coding RNAs. MiRNAs can function as tumour suppressors and oncogenes, and recent evidence indicates that are also involved in the control of drug resistance. For example: miR-21 modulates gemcitabine-induced apoptosis in cholangiocharcinoma cell lines, while experimental over-expression of miR-15b and miR-16 sensitizes a vincristine-resistant gastric cancer cell line by targeting Bcl-2 . In addition, in two ovarian cancer cell lines it has been recently demonstrated that miR-27a and miR-451 regulate P-glycoprotein expression, a major effector of drug resistance. 

We hypothesize that miRNAs also control the chemosensitivity of breast cancer cells to doxorubicin. To test this hypothesis we have generated derivatives with decreasing sensitivity to doxorubicin from minimally transformed mammary epithelial cells and their miRNA signature has been obtained. Current work aims to establish the contribution of each miR to the drug resistance phenotype.