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Richer Lab

 

Contacts:


RC1 North  5th Floor P18-5127
Ph. 303 724-3735 office 303 724-3711 lab
Email:   jennifer.richer@ucdenver.edu

Research Interests:  


Hormone receptor action and microRNAs that differ in receptor positive versus negative breast and gynecologic cancers and how they affect receptor expression, action, and epithelial to mesenchymal transition.

The goal of the lab is to further understand how hormone receptors and microRNAs influence the clinical behavior of breast and gynecologic cancers so that we can ultimately manipulate them with novel therapeutic agents.

Current lab focus:


•    The role of androgen receptor (AR) in both estrogen receptor alpha (ER) positive and negative breast cancer. We recently discovered that the ratio of AR to ER protein in breast cancers may play a role in response to traditional ER directed endocrine therapies such as tamoxifen and aromatase inhibitors.  We find that a new generation anti-androgen that acts by excluding AR from the nucleus, has anti-tumor activity in vivo in both ER+ and ER- breast cancers that retain AR expression. Our efforts in the laboratory recently led to the initiation of a phase 1 clinical trial in breast cancer with the anti-androgen enzalutamide which has been demonstrated to be effective in castrate resistant prostate cancer.

•    The role of microRNAs in breast and gynecologic cancers. Previous studies in the lab have identified specific microRNAs that are different in ER+ versus negative breast cancers. ER+ breast cancers have much higher levels of Dicer and express more abundant and higher levels of miRNAs in general. We have identified specific miRNAs that influence the clinical behavior of women’s cancers by affecting hormone receptor status, loss of epithelial characteristics, gain of mesenchymal and neuronal traits, tumor metabolism and chemosensitivity. Our goal is to conduct further pre-clinical studies to evaluate the potential therapeutic value of specific microRNA based therapies for aggressive breast, endometrial and ovarian cancers in preclinical models.

Specific projects:


1)    To understand our novel observation that inhibiting AR nuclear localization affects the activity of ER and estrogen-mediated breast cancer growth, we will conduct mechanistic molecular assays with agents that exclude AR from the nucleus and study the activity of ER. Additionally we are testing AR inhibitors in combination with other breast cancer targeted therapies in pre-clinical models of the various subtypes of breast cancer.
2)    miR-200c is high in well-differentiated ER+ breast cancers but low in poorly differentiated cancers. We have determined that miR-200c targets and suppresses many mesenchymal and neuronal genes and their protein products that should not be on in epithelial cells, but are inappropriately expressed in the poorly differentiated ER- types of breast cancers that have undergone EMT and exhibit very aggressive behavior. We find that restoration of miR-200c restores anoikis sensitivity, enhances chemosensitivity, and reduces migration and invasion. In ovarian cancer we observe that inducible miR-200c significantly reduces tumor burden and enhances sensitivity to paclitaxel.  Our recent efforts seek to understand which miRNA targets rapidly change to influence anoikis resistance, a particular step in the metastatic cascade, that is relatively understudied, but very important as it allows cells to survive as the leave their proper environment and invade through stroma and survive in the lymph and vasculature during metastasis.
3)    In contrast to miR-200c (which is high in ER+ breast cancers), miR-221/222 is high in ER negative breast cancers and it directly targets ER and Dicer itself. We now seek to determine if the combination of restoring miR-200c and inhibiting the activity of miR-221/222 will reprogram the most aggressive triple negative breast cancers into tumors that look and behave like their more treatable and less aggressive ER+ counterparts.
4)    As part of our project in the Program Project Grant to study the Function of the Normal Mammary Gland, we found that many microRNAs decrease during the transition from late pregnancy to lactation. We postulate that a decline in specific miRNAs allows rapid control of milk protein production and fatty acid synthesis. miR-150 was the most dramatically decreased during this time period. Interestingly, miR-150 is one of 4 miRNAs that is consistently lower in 8 different transgenic models of mammary gland cancer. We perfomed in situ hybridization for this miRNA in clinical breast cancer samples and indeed find that it is lost in tumor but highly expressed in adjacent normal (non-involved) epithelium. To determine the role of this miRNA in mammary gland development and tumorigenesis, we are crossing mice with floxed miR-150 with BLG-Cre and MMTV-Neu mice.

Current Trainees: 


Nicholas D’Amato, Ph.D. – postdoctoral fellow
Rick Heinz, B.S. – Cancer Biology Graduate Program Doctoral Candidate


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Select Publications:
1.  Cochrane DR, Spoelstra NS, Nordeen SK and JK Richer.  MicroRNA-200c Mitigates Invasiveness and Restores Sensitivity to Microtubule-Targeting Chemotherapeutic Agents. MOLECULAR CANCER THERAPEUTICS. 2009 8(5):1055-66. PMID: 19435871


2.  Cochrane DR., Howe EN, Spoelstra NS and JK. Richer Loss of miR-200c:  A Marker of Aggressiveness and Chemoresistance in Female Reproductive Cancers. J. ONCOLOGY3. Wright J, Richer JK and Goodall GJ. MicroRNAs and EMT in mammary cells and breast cancer. J Mammary Gland Biol Neoplasia. 15(2):213-23. 2010. 


4.  Cittelly DM, Richer JK, Sartorius CA.  Ovarian steroid hormones: what's hot in the stem cell pool? Breast Cancer Res. 2010. 12(4):309. 


5.  Cochrane DR, Cittelly DM and JK Richer. Steroid Receptors and MicroRNAs:  Relationships Revealed. STEROIDS. 2011. 76 (1-2):1-10.


7. Cochrane DR, Cittelly DM, Howe EH., Spoelstra NS, McKinsey EL, LaPara K, Elias A, Yee D, and JK Richer. MicroRNAs Link Estrogen Receptor alpha Status and Dicer Levels in Breast Cancer. HORMONES AND CANCER. 2010. 1(6): 306-319. PMID:21761362


8.  Howe, E. N. Dawn R. Cochrane and J.K. Richer. Targets of miR-200c mediate suppression of cell motility and anoikis. BREAST CANCER RESEARCH. 2011 Apr 18;13(2):R45. PMID: 21501518. *Highlighted by DC Radisky BREAST CANCER RESEARCH  Jun 10;13(3):110


9.   Cochrane, D.R, Spoelstra NS, Richer JK.  The role of miRNAs in progesterone action.  MOL CELL ENDO. 2011.  121(10) 361-6. PMID:  21946298


10.  Cochrane, D. R. B. M. Jacobsen, E.N. Howe, D. L. Bain and J. K. Richer. Progestin regulated miRNAs that mediate progesterone receptor action in breast cancer. MOL CELL ENDO. Jan 18 2012 Jan 18 epub ahead of print. PMID: 22330642


11.  Howe EN, Cochrane DR and Richer JK. The miR-200 and miR-221/222 miRNA Families: Opposing Effects on Epithelial Identity. J of MAMMARY GLAND BIOLOGY AND NEOPLASIA. 2012 Feb 17 epub ahead of print PMID: 22330642.


12.  Cittelly D. M., J. Finlay-Schultz, E.N. Howe, N.S. Spoelstra, S. Daddario-Axlund, P. Hendricks, B.M. Jacobsen, C.A. Sartorius1 and J. K. Richer.  Progestin suppression of miR-29 potentiates dedifferentiation of breast cancer cells via KLF4. ONCOGENE. 2012 Jul 2. PMID:  22751119


13.  Cittelly, D.M. Irina Dimitrova, Erin N. Howe, Dawn R. Cochrane, Annie Jean, Nicole Spoelstra, Xian Liu, Russell R. Broaddus, Monique A. Spillman, and Jennifer K. Richer. Restoration of miR-200c to ovarian cancer reduces tumor burden and increases sensitivity to paclitaxel. In Press Mol Cancer Ther. May 2012.


14.  Howe EN, Cochrane DR, Cittelly DM and Richer JK. miR-200c targets a TrkB/NTF3 autocrine signaling loop to suppress anoikis resistance in breast cancer. Submitted.


15.  Dawn R. Cochrane, Sebastian Bernales, Britta M. Jacobsen, Diana M. Cittelly,  Erin N. Howe,  Nicholas C. D’Amato,  Nicole S. Spoelstra,  Annie Jean,  Paul Jedlicka,  Kathleen C. Torkko,  Andy Protter,  Anthony D. Elias and J. K. Richer. Enzalutamide Inhibits Proliferation in Androgen Receptor Positive Breast Cancer Models. Submitted.