bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A096: MT-SP2/TMPRSS4 upregulates uPA gene expression through JNK signaling activation to induce cancer cell invasion
Authors: Lee Yunhee , Min Hye-Jin , Lee Hana , Zhao Xue-Feng , Park Young-Kyu , Kim Semi 
Published: May 2015

Abstract
The invasive nature of tumor cells is critical for cancer metastasis. Urokinase-type plasminogen activator (uPA) is a well-known serine protease involved in normal tissue remodeling, such as wound healing, and in pathological events, such as invasion and metastasis. Increased levels of uPA correlate with invasive properties and poor prognosis in breast, lung, stomach, bladder, colon, prostate and ovarian cancers. MT-SP2/TMPRSS4 is a novel type II transmembrane serine protease that is highly expressed in pancreatic, colon, and other cancer tissues. Previously, we demonstrated that MT-SP2/TMPRSS4 mediates tumor cell invasion, migration, and metastasis. However, the mechanisms by which MT-SP2/TMPRSS4 contributes to invasion are not fully understood. Here, we demonstrated that MT-SP2/TMPRSS4 induced the transcription of the uPA gene through activating the transcription factors Sp1, Sp3, and AP-1 in mainly a JNK-dependent manner and that the induction of uPA was required for MT-SP2/TMPRSS4-mediated cancer cell invasion and signaling events. In addition, the uPA receptor was involved in MT-SP2/TMPRSS4-induced signaling activation and subsequent uPA expression probably through its association with TMPRSS4 on the cell surface. Immunohistochemical analysis showed that uPA expression was significantly correlated with MT-SP2/TMPRSS4 expression in human carcinomas. These observations suggest that MT-SP2/TMPRSS4 is an important regulator of uPA gene expression; the upregulation of uPA by TMPRSS4 contributes to invasion and may represent a novel mechanism for the control of invasion.
Citation Format: Yunhee Lee, Hye-Jin Min, Hana Lee, Xue-Feng Zhao, Young-Kyu Park, Semi Kim. MT-SP2/TMPRSS4 upregulates uPA gene expression through JNK signaling activation to induce cancer cell invasion. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr A096.
Abstract A108: Distinct immune suppressive myeloid cell populations are induced by hypoxic mammary tumors and differentially promote metastatic tumor growth
Authors: Hamilton Melisa J. , Bosiljcic Momir , LePard Nancy E. , Harbourne Bryant T. , Krystal Gerald , Bennewith Kevin L. 
Published: May 2015

Abstract
Some primary tumors induce the accumulation of myeloid cells in distant tissues, and a role for these cells in promoting metastasis is emerging. However, the identity and function of these myeloid cells in metastatic breast cancer is unclear. Using transplantable and spontaneous metastatic mammary tumor models, we have found that immune suppressive CD11b+Gr1+ myeloid-derived suppressor cells (MDSCs) and CD11b+F4/80+Gr1- macrophages (MΦs) accumulate in the spleens and lungs of tumor-bearing mice due to proteins secreted by poorly oxygenated (hypoxic) cells in primary tumors. We also found that immunosuppressive MDSCs remain elevated in the lungs for several weeks after surgical resection of the primary tumor, and that these MDSCs profoundly enhance subsequent pulmonary metastatic growth.
To decrease MDSC levels in tissues, we therapeutically targeted hypoxic tumor cells or used all-trans retinoic acid (ATRA) to differentiate immature MDSCs into mature MΦs. Targeting hypoxic tumor cells or ATRA treatment both decreased MDSC levels in tissues, although ATRA-treated mice had more MΦs and significantly more lung metastases than untreated mice. Consistent with these data, we found that MΦs were 30-fold more potent suppressors of T cell-mediated immune responses than MDSCs on a per cell basis, and that MΦs and MDSCs suppress via different reactive oxygen species (ROS)-mediated mechanisms.
Taken together, these data suggest that hypoxia-mediated accumulation of MDSCs in the lungs can have long-lasting implications for the growth of secondary metastatic tumors after treatment. However, due to the immune suppressive function of MΦs, our data caution against inducing the terminal differentiation of MDSCs into MΦs for breast cancer treatment. These studies support the development of therapies to enhance anti-tumor immunity by targeting hypoxic tumor cells, MDSCs, and MΦs for the treatment of metastatic breast cancer.
Citation Format: Melisa J. Hamilton, Momir Bosiljcic, Nancy E. LePard, Bryant T. Harbourne, Gerald Krystal, Kevin L. Bennewith. Distinct immune suppressive myeloid cell populations are induced by hypoxic mammary tumors and differentially promote metastatic tumor growth. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr A108.
Abstract B004: Expansion of lineage negative, CD24high, CD61+ mammary cells is an early step in mammary tumorigenesis in NRL-TGFalpha and MMTV-c-neu but not MMTV-c-myc models of luminal breast cancer
Authors: Zhdankin Olga , Bomier Melanie , Parke Donna , Holy Jon , Rose-Hellekant Teresa 
Published: May 2015

Abstract
Our goal was to define the balance of normal, healthy mammary epithelial cell subpopulations, including putative stem, progenitor and mature cells, in mouse models of luminal breast cancer prior to tumor development. We isolated mammary cells using flow cytometric analysis, first by removing immune cells through negative lineage selection followed by labeling of remaining cells with CD24, CD61 and CD49f fluorescently tagged antibodies. We distinguished the presence of cell subpopulations and determined relative fractions of cells with expression patterns of enriched presumptive luminal progenitor cells (CD24 high, CD61positive), mature luminal cells (CD24high, CD61positive) and mammary stem cells (CD24 medium, CD49f high). Mammary glands from 3-4 month TGFalpha mice contained similar fractions of mammary cell subpopulations as wild type mice but at 7-8 month TGFalpha mice had an expanded CD24 high CD61positive fraction associated with hyperplasias and tumors. Four-month-old c-neu mice had expanded CD24 medium, CD49f high cell fractions and by the time tumors developed, both nontumorous glands and tumors also displayed an expanded CD24 high, CD61+ cell fraction. The cell surface marker expression pattern of mammary cells was unique in c-myc mice in that CD24 high (luminal) versus CD24 medium (myoepithelial) populations were not distinguishable at any time point. Our results indicate that early phases of tumorigenesis can be recognized by the disproportion presence of otherwise “normal” epithelial cell subpopulations or by the presence of novel subpopulations.
Citation Format: Olga Zhdankin, Melanie Bomier, Donna Parke, Jon Holy, Teresa Rose-Hellekant. Expansion of lineage negative, CD24high, CD61+ mammary cells is an early step in mammary tumorigenesis in NRL-TGFalpha and MMTV-c-neu but not MMTV-c-myc models of luminal breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr B004.
Abstract B009: A role for receptor tyrosine kinase crosstalk in a Met-dependent model of triple-negative breast cancer
Authors: Sung Vanessa , Knight Jennifer F. , Park Morag 
Published: May 2015

Abstract
Triple-negative (TN) breast cancers, which include the basal-like and claudin-low subtypes, account for up to 20% of breast cancer cases. TN breast cancers lack expression of therapeutic targets HER2 and estrogen receptors and are correlated with poor prognosis. In human breast cancer, elevated levels of MET are correlated with TN subtypes and poor outcome. The Met receptor tyrosine kinase (RTK) is a cell surface protein that, upon activation by its ligand hepatocyte growth factor (HGF), initiates a program of cell survival, migration, and invasive growth. To investigate the role of Met in breast tumorigenesis, we have used two mouse models in which mammary specific expression of an oncogenic variant of Met is driven by the MMTV promoter (Metmt). Metmt mice develop mammary tumors with a long latency and display features of basal-like breast cancer. As loss of function mutations in TP53 are found in ~80% of TN breast cancers, we have also generated Metmt mice with conditional deletion of Trp53 in the mammary gland (Metmt;p53-), which results in accelerated tumorigenesis and gene expression profiles that more closely resemble that of the claudin-low subtype of TN breast cancer.
The present work aims to elucidate how Met promotes mammary tumor development and whether this involves regulation of tumor-initiating cells (TICs). TICs have emerged as a key concept in prevailing models of tumor development, and are thought to drive tumorigenesis as well as contribute to disease relapse. To study TICs in our mouse models, we employed the sphere-forming assay, which enriches for TICs based on their stem-like ability to survive, propagate, and self-renew in suspension as spheroid structures (tumorspheres). Tumorspheres cultured from both tumor models express constitutively active Met. Upon treatment with Met inhibitor, Metmt tumorspheres are drastically reduced in both number and size. In contrast, Metmt;p53- tumorspheres are insensitive to Met inhibition, suggesting that other signals compensate for the loss of Met activity. It has been shown that Met can crosstalk with other RTKs such as EGFR. Therefore we hypothesize that activation of an alternative RTK signalling pathway is compensating for loss of Met signalling in Metmt;p53- tumorspheres.
The molecular events that lead to TN breast cancers are poorly understood. Validating a role for Met in TICs and identifying key cooperating pathways involved in the pathogenesis of triple negative breast cancers could provide information for new therapeutic targets.
Citation Format: Vanessa Sung, Jennifer F. Knight, Morag Park. A role for receptor tyrosine kinase crosstalk in a Met-dependent model of triple-negative breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr B009.
Abstract B013: Neuregulin signaling in development and transformation of the luminal breast epithelium
Authors: Vaught David B. , Hicks Donna , Cook Rebecca 
Published: May 2015

Abstract
The goal of these studies is to determine how combined loss of ErbB3 and ErbB4 impact the normal and transformed luminal population of the breast epithelium. Although little is known regarding the role of ErbB3 in luminal breast cancers, and even less about ErbB4, we have shown that ErbB3 and ErbB4 (the neuregulin receptors) are required for growth and survival of the two major luminal mammary epithelial cell types, the ductal luminal mammary epithelium, and the milk-producing alveolar mammary epithelium. However, as both ErbB3 and ErbB4 are capable of binding to neuregulins and heterodimerizing with other ErbB family members, there is evidence that ErbB4 may compensate for loss of ErbB3, and vice versa. Further, given that ErbB3 and ErbB4 are uniquely required within the luminal breast epithelium during phases of extreme physiological proliferation (i.e., puberty and pregnancy, respectively) it is likely that the neuregulin receptors drive cell growth and survival of breast cancers derived from the luminal breast epithelium. We hypothesize that elimination of NRG signaling by combined loss of ErbB3 and ErbB4 would prevent expansion of the mammary epithelium in response to physiological cues (i.e. pregnancy) and pathological cues (oncogene expression). Our early studies demonstrate loss of ErbB3 expansion of the alveolar epithelium during pregnancy, decreased expression of genes encoding milk proteins, and decreased milk delivery to nursing pups. This is similar to what is seen in ErbB4-deficient mammary glands. We are currently studying the ErbB3-dependnet molecular mechanisms required for expansion of the alveolar epithelium during pregnancy, and are generating mice that lack ErbB3 and ErbB4 in the alveolar mammary epithelium. We anticipate that combined gene targeting of ErbB3 and ErbB4 will cause a more pronounced lactational deficit.
Citation Format: David B. Vaught, Donna Hicks, Rebecca Cook. Neuregulin signaling in development and transformation of the luminal breast epithelium. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr B013.
Abstract B025: The role and regulation of SOX7 in breast cancer
Authors: Stovall Daniel B. , Wan Meimei , Miller Lance D. , Cao Paul , Zhang Qiang , Stampfer Martha , Liu Wennuan , Xu Jianfeng , Sui Guangchao 
Published: May 2015

Abstract
Loss of tumor suppressors by both epigenetic silencing and genetic deletion contributes to the development and progression of breast cancer. SOX7 is an important developmental transcription factor and its downregulation has been reported in tumor tissues and cell lines of prostate, colon and lung cancers. Our current study demonstrates that SOX7 mRNA and protein expression are downregulated in breast cancer tissues and cell lines compared to adjacent normal tissues and nontumorigenic cells, respectively. Further, we show that both hypermethylation of the SOX7 promoter and microRNAs contribute to SOX7 downregulation. SOX7 silencing by shRNAs in nontumorigenic immortal breast cells leads to increased proliferation and invasion, and they form structures resembling that of breast cancer cells in a three-dimensional culture system. Conversely, ectopic SOX7 expression inhibits proliferation, and invasion of breast cancer cells in vitro and tumor growth in vivo. Importantly, we discovered that SOX7 transcript levels positively correlated with clinical outcome of 674 breast cancer patients. Collectively, our data suggest that SOX7 acts as a tumor suppressor in breast cancer. SOX7 expression is likely regulated by multiple mechanisms and potentially serves as a prognostic marker for breast cancer patients.
Citation Format: Daniel B. Stovall, Meimei Wan, Lance D. Miller, Paul Cao, Qiang Zhang, Martha Stampfer, Wennuan Liu, Jianfeng Xu, Guangchao Sui. The role and regulation of SOX7 in breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr B025.
Abstract B057: Treatment with anti-human GP88/progranulin antibody restores tamoxifen sensitivity to tamoxifen-resistant breast cancer cells
Authors: Serrero Ginette , Dong Jianping , Yue Binbin , Hicks David , Hayashi Jun 
Published: May 2015

Abstract
The 88 kDa glycoprotein GP88 (Progranulin, PCDGF, acrogranin) is the largest member of the granulin/epithelin family consisting of 7.5 repeats of a highly conserved 12-cysteine granulin/epithelin motif. Our laboratory demonstrated the role of GP88 as an autocrine growth and survival factor in breast cancer: 1) GP88 expression increases with tumorigenesis; 2) inhibition of GP88 expression by antisense transfection in MDA-MB-468 cells inhibited tumor formation in nude mice by 90%; 3) in ER+ breast cancer cells, GP88 stimulates proliferation and its overexpression confers estrogen independence; 4) GP88 is a strong survival factor that confers resistance to anti-estrogen and aromatase inhibitors in ER+ breast cancer; 5) GP88 is expressed in 80% invasive ductal carcinoma and 60% of ductal carcinoma whereas it is negative in benign lesions and normal mammary epithelial cells; 6) pathological studies with 530 cases of ER+ invasive ductal carcinoma (ER+ IDC) showed that GP88 tumor expression is a prognostic indicator of recurrence and death in early stage breast cancer patients with high GP88 tissue expression associated with a 4-fold increase in the risk of recurrence; 7) GP88 is secreted and can be detected in the serum of breast cancer patients at an increased level when compared to healthy subjects. Based on these results GP88 represents an ideal therapeutic and diagnostic target in breast cancer. We have characterized a neutralizing anti-GP88 monoclonal antibody that has been expressed in recombinant form and named AG1. AG1 inhibits GP88 biological effect such as migration and invasion of breast cancer cells in a dose-dependent fashion. Since GP88 is a prognostic factor of recurrence in ER+ IDC, the present study investigates the effect of AG1 on the tumor development and tamoxifen responsiveness of tamoxifen resistant ER+ breast cancer cell line (TamR) injected in nude mice. We show that AG1 alone inhibited tumor growth of TamR cells injected into nude mice while tamoxifen alone had moderate effect. Interestingly, AG1 administered in combination with tamoxifen, inhibited by more than 50% tumor formation of TamR cells.
These data suggest that inhibiting GP88 provide a novel and alternate pathway for restoration of tamoxifen sensitivity in ER+ breast cancer.
This works is supported by grant 2R44CA124179 and contract HHSN261201200060C from the National Cancer Institute.
Citation Format: Ginette Serrero, Jianping Dong, Binbin Yue, David Hicks, Jun Hayashi. Treatment with anti-human GP88/progranulin antibody restores tamoxifen sensitivity to tamoxifen-resistant breast cancer cells. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr B057.
Abstract B071: Targeting the antiapoptotic protein Mcl-1 in luminal B breast cancers
Authors: Williams Michelle M. , Fesik Steve , Hicks Donna , Cook Rebecca S. 
Published: May 2015

Abstract
In an effort to improve therapeutic tumor cell killing in luminal B breast cancers, we are investigating the combination of endocrine therapies with targeted inhibition of pro-survival proteins of the Bcl2 family, including Bcl2, Bcl-xL, and Mcl-1. Bcl2-family proteins are often overexpressed in breast cancers and are associated with tumor progression, therapeutic resistance, and poor patient survival. These proteins function by sequestering pro-apoptotic BH3-only proteins (BIM, BID, Noxa and Puma), thus inhibiting caspase-dependent apoptosis. We found Mcl1 gene amplification in 15/133 luminal B breast tumors (11%) curated through the Cancer Genome Atlas (TCGA), and Bcl2l1 (encoding Bcl-xL) gene amplification in 1/133 luminal B breast tumors, although Bcl2l1 mRNA was upregulated in 19/133 samples. Bcl2 was not amplified or overexpressed in TCGA-curated luminal B breast tumors. The BH3 mimetic ABT-263, which specifically binds Bcl2 and Bcl-xL, increased tumor cell killing in 3 out of 4 estrogen-deprived luminal B human breast cancer cell lines. However, ZR75-1 cells, which are Mcl1 gene amplified, were resistant to ABT-263. Further, Mcl-1 protein upregulation was induced in HCC-1428 and T47D cells treated with ABT-263, suggesting that cells may use Mcl-1 upregulation to partially mitigate the effects of Bcl-xL targeting with ABT-263. Mcl-1 knockdown using an shRNA approach, decreased cell growth and increased caspase-dependent apoptosis, and increased sensitivity to ABT-263 in 4 of the 4 cell lines tested, including ZR75-1 cells. We used long-term estrogen withdrawal (LTED) to model the sustained response of breast cancer cells to aromatase inhibitors (e.g., exemestane). As compared to parental breast cancer cell lines under estrogen withdraw conditions, LTED populations drastically increased protein levels of Mcl-1. Future experiments will be aimed at assessing the impact of Mcl-1 depletion on ABT-263-treated LTED populations. We predict that combined inhibition of Bcl-2, Bcl-xL and Mcl-1 will improve response of cells to estrogen deprivation. In summary, these preliminary studies suggest that BH3 mimetics targeting Bcl-2 family proteins may be therapeutically efficacious in endocrine-refractory luminal B breast tumors, and support future endeavors to generate BH3-mimetics specifically targeting Mcl-1.
Citation Format: Michelle M. Williams, Steve Fesik, Donna Hicks, Rebecca S. Cook. Targeting the antiapoptotic protein Mcl-1 in luminal B breast cancers. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr B071.
Abstract B097: Innate immune response to cell death in the post-partum mammary gland increases malignancy of parity-associated mammary tumors
Authors: Stanford Jamie C. , FIngleton Barbara , Owen Phil , Cook Rebecca S. 
Published: May 2015

Abstract
Pregnancy-associated breast cancers (PABCs) are associated with decreased overall survival as compared to breast cancers not associated with pregnancy, due in large part to macrophage-dependent changes that occur in the mammary gland during post-lactational involution. We have used the MMTV-PyVmT spontaneous mouse mammary tumor model to demonstrate that, while tumor latency, growth rate and burden were similar in parous and nulliparous mice, metastasis of parity-associated mammary tumors was increased 17-fold over tumors from age-matched virgin nulliparous mice. Th2 cytokines produced in the tumor microenvironment (TME) correlate with increased tumor malignancy. We found profoundly upregulated expression of Th2 cytokines in parity-associated mammary tumors over tumors from nulliparous mice, including interleukin (IL)-4, IL-13, and IL-10. Serum harvested from parous mice induced tumor cell invasion to a greater extent than serum from nulliparous mice. MerTK, a receptor tyrosine kinase (RTK) of the Tyro-3/Axl/MerTK family expressed in M2c tissue macrophages and TAMs, suppresses Th1 cytokine production and promotes Th2 cytokine expression. MerTK expression was profoundly upregulated in parous mammary tumors during post-lactational involution, similar to previous findings of MerTK upregulation in normal mammary glands during involution. Although loss of MerTK did not affect latency or growth of parity-associated mammary tumors, we observed decreased metastasis and Th2 cytokine production in MerTK-deficient tumors. Serum from MerTK-deficient parous mice induced tumor cell invasion to a lesser extent than serum from parous wild-type mice. These results demonstrate that MerTK enhances malignancy of parity-associated mammary tumors, and may represent a therapeutic target to improve the outcome in PABC.
Citation Format: Jamie C. Stanford, Barbara FIngleton, Phil Owen, Rebecca S. Cook. Innate immune response to cell death in the post-partum mammary gland increases malignancy of parity-associated mammary tumors. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr B097.