Photo of Doris Germain

Doris Germain

  • ASSOCIATE PROFESSOR Medicine, Hematology and Medical Oncology
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Training Areas

Education

  • B.Sc., McGill University
    Microbiology and Immunology

  • Ph.D., Montreal University
    Biochemistry

Biography

    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.

Research

Specific Clinical/Research Interest:
Role of cyclins in prognosis of breast cancer; pregnancy-associated breast cancer; role of estrogen receptor in the mitochondria.

Postdoctoral Fellows: Yuki Ishii, Urvashi Bahadur, Harish Chander, Luena Papa

Research Personnel: Max Halpern
 
Summary of Research Studies:

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 ofthe 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 breast cancers 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.


Publications

Radke S, Chander H, Schafer P, Meiss G, Kruger R, Schulz JB, Germain D. Mitochondrial protein quality control by the proteasome involves ubiquitination and the protease Omi. J. Biol. Chem 2008; 283: 12681.

Ishii Y, Waxman S, Germain D. Tamoxifen stimulates the growth of cyclin D1 overexpressing breast cancer cells by promoting the activation of STAT3. Cancer Research 2008; 68(3): 852.

Umanskaya K, Radke S, Chander H, Monardo R, Xu X, Pan Z, O'Connell MJ, Germain D. Skp2B stimulates mammary gland development by inhibiting the repressor of the estrogen receptor REA. Molecular and Cellular Biology 2007; 27: 7615-7622.

Germain D, Frank DA. Targeting the cytoplasmic and nuclear functions of STAT3 for cancer therapy. Clinical Cancer Research 2007; 13: 5665-5669.

Ishii Y, Waxman S, Germain D. Targeting the Ubiquitin-proteasome Pathway in Cancer Therapy. Anti-cancer agents in Medicinal Chemistry 2007; 3: 365-369.

Ishii Y, Pirkmaier A, Mandeli J, Alavez J, Frank J, Keselman I, Logothetis D, O'Connell MJ, Waxman S, Germain D. Cyclin D1 overexpression and response to Bortezomib in a breast cancer model. J. Natl. Cancer Inst 2006; 98: 1238-1247.

Russell A, Thompson MA, Hendley J, Trute L, Armes J, Germain D. Cyclin D1 and D3 associate with the SCF complex and are coordinately elevated in breast cancer. Oncogene 1999 Mar; 18(11).

Russell A, Hendley J, Germain D. Inhibitory effect of p21 in MCF-7 cells is overcome by its coordinated stabilization with D-type cyclins. Oncogene 1999 Nov; 18(47).

Germain D, Russell A, Thompson A, Hendley J. Ubiquitination of free cyclin D1 is independent of phosphorylation on threonine 286. The Journal of biological chemistry 2000 Apr; 275(16).

Ganiatsas S, Dow R, Thompson A, Schulman B, Germain D. A splice variant of Skp2 is retained in the cytoplasm and fails to direct cyclin D1 ubiquitination in the uterine cancer cell line SK-UT. Oncogene 2001 Jun; 20(28).

Zancai P, Dal Col J, Piccinin S, Guidoboni M, Cariati R, Rizzo S, Boiocchi M, Maestro R, Dolcetti R. Retinoic acid stabilizes p27Kip1 in EBV-immortalized lymphoblastoid B cell lines through enhanced proteasome-dependent degradation of the p45Skp2 and Cks1 proteins. Oncogene 2005 Apr; 24(15).

Pirkmaier A, Yuen K, Hendley J, O'Connell MJ, Germain D. Cyclin d1 overexpression sensitizes breast cancer cells to fenretinide. Clinical cancer research : an official journal of the American Association for Cancer Research 2003 May; 9(5).

Pirkmaier A, Dow R, Ganiatsas S, Waring P, Warren K, Thompson A, Hendley J, Germain D. Alternative mammary oncogenic pathways are induced by D-type cyclins; MMTV-cyclin D3 transgenic mice develop squamous cell carcinoma. Oncogene 2003 Jul; 22(28).

Benzeno S, Narla G, Allina J, Cheng GZ, Reeves HL, Banck MS, Odin JA, Diehl JA, Germain D, Friedman SL. Cyclin-dependent kinase inhibition by the KLF6 tumor suppressor protein through interaction with cyclin D1. Cancer research 2004 Jun; 64(11).

Radke S, Pirkmaier A, Germain D. Differential expression of the F-box proteins Skp2 and Skp2B in breast cancer. Oncogene 2005 May; 24(21).

Chander H, Halpern M, Resnick-Silverman L, Manfredi JJ, Germain D. Skp2B attenuates p53 function by inhibiting prohibitin. EMBO reports 2010 Mar; 11(3).

Ishii Y, Papa L, Bahadur U, Yue Z, Aguirre-Ghiso J, Shioda T, Waxman S, Germain D. Bortezomib enhances the efficacy of fulvestrant by amplifying the aggregation of the estrogen receptor, which leads to a proapoptotic unfolded protein response. Clinical cancer research : an official journal of the American Association for Cancer Research 2011 Apr; 17(8).

Germain D. Skp2 and Skp2B team up against Rb and p53. Cell division 2011; 6(1).

Germain D. Skp2 and Skp2B team up against Rb and p53. Cell division 2011; 6(1).

Chander H, Halpern M, Resnick-Silverman L, Manfredi JJ, Germain D. Skp2B overexpression alters a prohibitin-p53 axis and the transcription of PAPP-A, the protease of insulin-like growth factor binding protein 4. PloS one 2011; 6(8).

Misra D, Adelson K, Halpern M, Jaffer S, Nagi C, Mandeli J, Bleiweiss I, Raptis G, Germain D. Correlation of Oncotype DX Recurrence Score with Cyclin D1 and ErbB2. Cancer Research ; 69 (Suppl).: 657.

Kerin K, Bahadur U, Halpern M, Hauptman E, Barginear M, Bleiweiss I, Ting J, Weltz C, Coomer C, Raptis G, Germain D. Wound fluid induces cancer cell growth: a mechanism for recurrence?. Cancer Research; 69 (Suppl): 694.

Germain D, Adelson K, Raptis G, Waxman S, Ishii I. Bortezomib enhances the efficacy of fulvestrant by promoting the aggregation of the ER in the cytoplasm. Cancer Research; 69 (Suppl): 813.

Germain D. Estrogen Carcinogenesis in Breast Cancer. Endocrine Clinics of North America 2011 Sept; 40(3): 473-84.

Adelson K, Germain D, Raptis G, Bira N. Aromatase Inhibitors, Anti-Estrogens and SERMS in the Treatment of Breast Cancer. Endocrine Clinics of North America 2011 Sept; 40(3): 519-32.

Papa L, Germain D. The estrogen receptor mediates a novel mitochondrial unfolded protein response. Journal of Cell Science 2011; 124: 1396.

Industry Relationships

Physicians and scientists on the faculty of the Icahn School of Medicine at Mount Sinai often interact with pharmaceutical, device and biotechnology companies to improve patient care, develop new therapies and achieve scientific breakthroughs. In order to promote an ethical and transparent environment for conducting research, providing clinical care and teaching, Mount Sinai requires that salaried faculty inform the School of their relationships with such companies.

Dr. Germain did not report having any of the following types of financial relationships with industry during 2013 and/or 2014: consulting, scientific advisory board, industry-sponsored lectures, service on Board of Directors, participation on industry-sponsored committees, equity ownership valued at greater than 5% of a publicly traded company or any value in a privately held company. Please note that this information may differ from information posted on corporate sites due to timing or classification differences.

Mount Sinai's faculty policies relating to faculty collaboration with industry are posted on our website at http://icahn.mssm.edu/about-us/services-and-resources/faculty-resources/handbooks-and-policies/faculty-handbook. Patients may wish to ask their physician about the activities they perform for companies.

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