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Baldwin Fund to support five breast cancer research projects and two lectures

SYRACUSE, N.Y.-- The Carol M. Baldwin Breast Cancer Research Fund Inc. is supporting five breast cancer research studies at Upstate Medical University with $250,000 in funding and two endowed lectures through its 2015 allocations program.

Since 2002, the fund has awarded Upstate researchers more than $3 million to further their studies into the cause of breast cancer. In addition to the grants, the Baldwin Fund sponsors two annual endowed lectureships focused on breast cancer developments. The Baldwin family dedicates their research grants and the endowed lectures in memory of women who have been affected by the disease.

“It is important to continue the search until a cure for breast cancer is discovered,” said Beth Baldwin, whose mother, Carol, a breast cancer survivor, founded the Baldwin Fund. “We appreciate the support we receive from everyone who participates in our events. Their continued support will help to further knowledge into the cause of this disease and will take us closer to finding a cure. We owe it to the women who have lost their lives to the disease and to those who have survived,” she said.

Studies receiving 2015 funding

- Targeting V-ATPase Subunit Isoforms for Breast Cancer Therapy. Dedicated in the memory of Karen Mortell

Principal Investigator: Stephan Wilkens, Ph.D., associate professor of biochemistry and molecular biology.

Evidence suggests that breast cancer invasiveness is correlated with high-level expression of V-ATPase on the tumor cells’ plasma membrane, making V-ATPase a potential drug target. Available V-ATPase inhibitors have shown promise with suppressing invasiveness in cultured cells, but the compounds’ toxicity prevents their therapeutic use. While isoforms offer the possibility of cancer specific V-ATPase inhibition, lack of structural information has limited structure based drug design so far. This study proposes to develop single domain antibodies (“nanobodies”) directed against specific isoforms to determine high resolution structure. The nanobodies potential as isoform specific V-ATPase inhibitors will be tested.

- Role of PP5 Phosphatase in Tamoxifen Resistance in Breast Cancer. Dedicated in memory of Jamie Lynn Batruch - The Alexander Family

Principal Investigator: Mehdi Mollapour, Ph.D., assistant professor of urology, biochemistry and molecular biology.

The serine/threonine protein phosphatase-5 (PP5) regulates several signaling cascades that are responsible for tumor initiation, progression and metastasis. PP5 is upregulated in breast cancer. Mollopour’s study has revealed that PP5 is hyperphosphorylated in tamoxifen resistant breast cancer cells compared to their non-resistant parent cells. Further analysis has revealed that the enzyme CK1 directly phosphorylates PP5 and consequently increases its phosphatase activity. Understanding the molecular mechanisms of CK1-PP5 signaling axis in tamoxifen resistant breast cancer will provide Mollapour and his colleagues with potential novel therapeutic targets for treating this disease.

- Role of Pim1 in Breast Cancer Progression. Dedicated in memory of Loretta M. Bregou and Katherine Bregou Grainger

Principle Investigator: Golam Mohi, PhD,  associate professor of pharmacology

In preliminary studies, Mohi has observed that the enzyme Pim1 expression is significantly increased in tumorigenic breast cancer cells compared with normal breast epithelial cells. Knockdown of Pim1 significantly inhibits the growth of both estrogen-receptor-positive (ER+) and triple-negative breast cancer cells. Also, treatment of TP-3654, a novel small molecule second-generation Pim kinase inhibitor, potently inhibits the growth of both of these breast cancer cells. His studies will define the role of Pim1 in the growth, survival, migration and invasion of breast cancer cells and will also test the efficacy of Pim kinase inhibitor TP-3654 against breast cancer cells, providing new insights into the biology of breast cancer and possibly identifying new therapeutic targets.

- Myo1e as a Tumor Promoter: Mechanisms and Therapeutic Potential. Dedicated in memory of Jeanelle Cross

Principal Investigator: Mira Krendel, Ph.D., associate professor of cell and developmental biology; Co-Investigator: Juntao Luo, Ph.D., assistant professor of pharmacology.

Myosin 1e (Myo1e) is a motor protein that regulates cell adhesion and migration and whose expression correlates with poor prognosis in patients with invasive breast cancer. The preliminary findings from Krendel’s team shows that Myo1e deletion increases tumor latency and reduces tumor growth and metastasis in a mouse model of breast cancer. This project will provide mechanistic insights into the molecular pathways leading to formation and metastasis of mammary tumors and serve as the basis for using Myo1e as a drug target in breast cancer.

Structural Basis for PAD2 Regulation of the MLL1 Core Complex. Dedicated in memory of Shirley Hall

Principal Investigator: Michael S. Cosgrove, Ph.D., associate professor of biochemistry and molecular biology.

Protein arginine deiminase-2 (PAD2) is one of the most highly upregulated genes in luminal breast cancer cells. Inhibition of PAD2 induces cell cycle arrest and apoptosis (death)  in cancer cells, but the molecular mechanismsinvolved are not understood. Cosgrove and his team discovered that PAD2 specifically targets the Mixed Lineage Leukemia-1 (MLL1) protein in breast cancer cells, a key master regulator of cell identity, suggesting that inhibition of PAD2 catalyzed citrullination of MLL1 may be a novel strategy for targeted breast cancer therapy. He and his team are addressing questions about the specificity of PAD2 with the long-term goal of developing novel targeted inhibitors for treatment of breast cancers.

Endowed lectures

- The first of the 2015 lectures will be held Wednesday, Nov. 11 at the Department of Surgery Grand Rounds. Shelley Hwang, M.D., professor of surgery, Division of Advanced Oncologic and GI Surgery at Duke University Medical Center, will present “Over-Diagnosis, Over-Treatment and Implications for the Earliest Breast Cancers.”

- Hironobu Sasano, M.D., Ph.D., professor and chair of the Department of Pathology, Tohoku University School of Medicine in Sendai, Japan, will present the Carol Baldwin Cancer Research Lecture Dec. 3 at 3 p.m. in the Medical Alumni Auditorium, Weiskotten Hall. In this presentation, Sasano will describe how estrogen stimulates breast tumor growth, addressing why estrogen-dependent breast cancer develops more often after menopause when the circulating estrogen levels are markedly low.  He also will discuss the association of obesity with breast carcinoma recurrence and development and explain how the drugs known as aromatase inhibitors work and the mechanism of aromatase inhibitor resistance. The lecture is open to the public.

Caption: Upstate Medical University researchers Juntao Luo, pictured, and Mira Krendel will use a Baldwin Fund grant to continue studies on a protein that impacts cancerous tumor growth.

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