Rebecca Chin Lab
Rebecca Chin, Ph.D.
Beth Israel Deaconess Medical Center
330 Brookline Avenue
Boston, MA 02215
The major goal of our laboratory is to understand the regulation of cancer growth and metastasis by the PI3K/Akt pathway, one of the most frequently deregulated signaling cascades in epithelial cancers. We are particularly interested in studying tumorigenesis of triple negative breast cancer, an aggressive form of breast cancer for which there is no effective targeted therapy. Another major area of our investigation is to explore how breast cancer cells develop acquired resistance to therapies targeting the Akt pathway. The ultimate goal of our research is to develop more effective therapies with lower toxicity for cancer patients.
Identification of Akt targets that regulate cancer growth, survival and metastasis
The three isoforms of Akt (Akt1-3) were originally thought to function redundantly in pathophysiology. It is now clear that they have specific signaling roles in modulating phenotypes associated with malignancy. We and others have previously demonstrated opposing functions of Akt1 and Akt2 in regulating breast cancer cell motility and metastasis. More recently, we have revealed a distinct role of Akt2 in PTEN-deficient tumor maintenance. We have developed a genome-wide, mass spectrometry-based proteomic strategy to identify novel Akt isoform-specific targets. Combining with RNAi and bioinformatics approaches, substrates discovered in the screens are used to delineate isoform-specific signaling networks that drive cancerous growth and metastasis. The goal of these studies is to identify novel biomarkers and targets for therapeutic interventions in different subtypes of breast cancer.
3D culture for uncovering Akt isoform-specific signaling in multiple cancer contexts
Do Akt isoforms have distinct functions in other aggressive tumors where the Akt pathway is hyperactive? In addition to breast cancer, our laboratory is examining distinct functions of Akt isoforms in other solid tumors. The major approach we are using is modulation of gene function in a temporally controlled manner in 3-dimensional culture system. The 3D system is employed to better recapitulate the microenvironment and morphology of tumors growing in vivo. We have found distinct functions of Akt isoforms in prostate, lung and ovarian cancer progression. Currently, we are dissecting the molecular mechanisms by which Akt isoforms regulate apoptosis, polarization and invasion, key events in cancer initiation and progression. We are using live cell imaging to examine the intracellular dynamics in a real-time manner.
Resistance mechanisms to targeted therapies in breast cancer
Recent clinical studies provide promising data that kinase inhibitor therapies have led to remarkable initial tumor responses in a variety of cancers. However, the tumor shrinkage is usually incomplete, and majority of patients inevitably relapse with tumor resistant to the inhibitor. Little is known about the adaptive signaling and genetic events that underling PI3K/Akt inhibitor resistance. To investigate mechanisms of acquired resistance in breast cancer extensively, we use genetically defined tumor lines to model resistance emergence in vitro and in vivo. We are also collaborating with clinical teams to study resistance development in tumor biopsies of breast cancer patients. These complementary approaches will provide insights for designing new mechanism-based inhibitors and combination strategies to circumvent resistance.
1. Chin YR, Yuan X, Balk SP, Toker A. PTEN-deficient tumors depend on Akt2 for maintenance and survival. Cancer Discov, 4:942 (2014) PMID: 24838891
• Cover Image of Cancer Discov Vol. 4, Num. 8 issue
2. Chin YR, Yoshida T, Marusyk A, Beck AH, Polyak K, Toker A. Targeting Akt3 signaling in triple-negative breast cancer. Can Res, 74:964 (2014) PMID: 24335962
• Highlighted as a “Very Good” finding by Arthur Mercurio: F1000Prime Biology
3. Toker A and Chin YR. Akt-ing up on SRPK1: oncogene or tumor suppressor? Mol Cell, 54:329 (2014) PMID: 24813709
4. Kazerounian S, Gerald D, Huang M, Chin YR, Udayakumar D, Zheng N, Oí’Donnell RK, Perruzzi C, Mangiante L, Pourat J, Phung T, Bravo-Nuevo A, Shechter S, McNamara S, DuHadaway J, Kocher ON, Brown L, Toker A, Prendergast GC and Benjamin LE. RhoB differentially controls Akt function in tumor cells and stromal endothelial cells during breast tumorigenesis. Can Res, 73:50 (2013) PMID: 23135917
5. Inuzuka H, Gao D, Finley L, Yang W, Wan L, Fukushima H, Chin YR, Zhai B, Shaik S, Lau AW, Wang Z, Gygi SP, Nakayama K, Teruya-Feldstein J, Toker A, Haigis MC, Pandolfi PP and Wei W. Acetylation-Dependent Regulation of Skp2 Function. Cell, 150:179 (2012) PMID: 22770219
6. Chin YR and Toker A. Akt isoform-specific signaling in breast cancer: Uncovering an anti-migratory role for palladin. Cell Adh Migr, 5:211-214 (2011) PMID: 21519185
7. Chin YR and Toker A. The actin bundling protein palladin is an Akt1-specific substrate that regulates breast cancer cell migration. Mol Cell, 38:333-344 (2010) PMID: 20471940
• Featured in Breast Cancer Network News
• Featured in a press release on the BIDMC website
• Highlighted as a “Must Read” finding by Brendan Manning: Faculty of 1000 Biology
8. Chin YR and Toker A. Akt2 regulates expression of the actin-bundling protein palladin. FEBS Lett, 584:4769-4774 (2010) PMID: 21050850
9. Chin YR and Toker A. Function of Akt/PKB signaling to cell motility, invasion and the tumor stroma in cancer. Cell Signal 21:470 (2009) PMID: 19110052