Doris Germain

Doris Germain, PhD

  • PROFESSOR | Medicine, Hematology and Medical Oncology
  • ASSOCIATE PROFESSOR | Oncological Sciences

Research Topics:

Cancer, Cell Cycle, Hormones, Mitochondria, Oncogenes, Protein Degradation, Protein Folding, Receptors

Our laboratory focuses on three aspects of breast cancer, first develop strategies to enhance the efficacy of hormonal therapy of breast cancer, second, understanding the role of pregnancy in the increased risk of breast cancer and thirdly elucidate the function of the estrogen receptor in the mitochondria.

Molecular profiling of breast cancers has revealed that there are at least 4 genetically distinct sub-types of breast cancers, namely luminal A, luminal B, erbB2 and basal-like. Luminal A and B are characterized by the presence of the estrogen receptor (ER), which is used clinically as a marker for endocrine therapy. Tamoxifen is the first drug that has been developed for the endocrine therapy of ER positive breast cancers. However, resistance to tamoxifen is frequent and several mechanisms have been proposed. Our laboratory focuses on the role of cyclin D1 in tamoxifen resistance. Cyclin D1 is a key regulator of the cell cycle progression from G1 into S phase. Overexpression of cyclin D1 is observed in 35-50% of breastcancers and is more frequent in luminal B breast cancers. We recently published the results supporting a model for the mechanism of tamoxifen resistance induced by cyclin D1 overexpression (Ishii et al. 2008, Cancer Research). We are currently focusing on developing alternative endocrine therapy for this sub-type of breast cancers using the ER down-regulator fulvestrant. Fulvestrant acts by promoting the proteasome-dependent degradation of the ER.

Recognition of a protein for degradation by the proteasome requires its ubiquitination. Linkage of ubiquitin to a protein involves the sequential action of an ubiquitin activating enzyme (E1), ubiquitin conjugating enzyme (E2) and ubiquitin ligase. The nature of the ubiquitin ligase required for the degradation of the ER following fulvestrant treatment remains to be determined and is currently being pursuit in our laboratory.


The second project in our laboratory focuses on defining the role of a novel ubiquitin ligase, SCF-Skp2B. Skp2B is overexpressed in breast cancers and in order to understand its function, we created transgenic mice that overexpressed Skp2B in the mammary glands. We published our observation that Skp2B leads to the degradation of a repressor of the ER termed REA. The elimination of REA leads to the activation of the ER and the hyper-proliferation of the mammary gland in mice. In addition, we found that the mammary glands of MMTV-Skp2B transgenic virgin animal resemble those of a pregnant wild-type female and that approximately 10% of mice develop mammary carcinoma. We currently aim at understanding the link between pregnancy-like phenotype observed in our mice and mammary carcinogenesis. We more recently published that Skp2B also leads to the degradation of prohibitin, a negative regulator of p53. Future directions include the elucidation of how Skp2B recognizes its substrates.


The third project focuses on the finding of an ubiquitin-dependent protein quality control of proteins of the mitochondria and of a retrograde-stress response that communicates the detection of stress in inter-membrane space of the mitochondria to the nucleus. Further, we found that this stress response is dependent on the transcriptional activity of the ER. Our findings highlight a novel mechanism by which cancer cells survive oxidative stress.

Multi-Disciplinary Training Area

Cancer Biology [CAB]


BSc, McGill University

PhD, Montreal University