scholarly journals Novel Antibodies Targeting MUC1-C Showed Anti-Metastasis and Growth-Inhibitory Effects on Human Breast Cancer Cells

2020 ◽  
Vol 21 (9) ◽  
pp. 3258
Author(s):  
Min Jung Kim ◽  
Jong Rip Choi ◽  
Nara Tae ◽  
Tae Min Wi ◽  
Kristine M. Kim ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Mammalian Cells ◽  
Type I ◽  
Breast Cancers ◽  
Human Breast ◽  
Cellular Functions ◽  
Multiple Cancer ◽  
Specific Antibodies ◽  
Therapeutic Development

Mucin1 (MUC1) is aberrantly glycosylated and overexpressed in various cancers, and it plays a crucial role in cancerogenesis. MUC1 is a type I membranous protein composed of α and β subunits. MUC1-α can be cleaved in cancers, exposing MUC1-β (MUC1-C). MUC1-C is involved with multiple cancer cellular functions, which makes it an attractive target for cancer treatment. However, its multifunctional mechanisms have not been fully elucidated and there has not been a successful therapeutic development against MUC1-C. Through a phage display process, we isolated the specific antibodies for the extracellular domain of MUC1-C. The relevant full IgG antibodies were produced successfully from mammalian cells and validated for their MUC1-C specificities through ELISA, dual FACS analysis, BLI assay, and confocal image analysis. In the comparison with reference antibody, elected antibodies showed characteristic bindings on target antigens. In the functionality assessment of high-ranking antibodies, SKM1-02, -13, and -20 antibodies highly inhibited invasion by triple-negative breast cancer (TNBC) cells and the SKM1-02 showed strong growth inhibition of cancer cells. Our results showed that these MUC1-C specific antibodies will be important tools for the understanding of MUC1 oncogenesis and are also highly effective therapeutic candidates against human breast cancers, especially TNBC cells.

scholarly journals Matrix degradation and cell proliferation are coupled to promote invasion and escape from an engineered human breast microtumor

2021 ◽  
Vol 13 (1) ◽  
pp. 17-29
Author(s):  
Emann M Rabie ◽  
Sherry X Zhang ◽  
Andreas P Kourouklis ◽  
A Nihan Kilinc ◽  
Allison K Simi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Cell Proliferation ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Type I ◽  
Matrix Degradation ◽  
Human Breast ◽  
Rate Of Invasion

Abstract Metastasis, the leading cause of mortality in cancer patients, depends upon the ability of cancer cells to invade into the extracellular matrix that surrounds the primary tumor and to escape into the vasculature. To investigate the features of the microenvironment that regulate invasion and escape, we generated solid microtumors of MDA-MB-231 human breast carcinoma cells within gels of type I collagen. The microtumors were formed at defined distances adjacent to an empty cavity, which served as an artificial vessel into which the constituent tumor cells could escape. To define the relative contributions of matrix degradation and cell proliferation on invasion and escape, we used pharmacological approaches to block the activity of matrix metalloproteinases (MMPs) or to arrest the cell cycle. We found that blocking MMP activity prevents both invasion and escape of the breast cancer cells. Surprisingly, blocking proliferation increases the rate of invasion but has no effect on that of escape. We found that arresting the cell cycle increases the expression of MMPs, consistent with the increased rate of invasion. To gain additional insight into the role of cell proliferation in the invasion process, we generated microtumors from cells that express the fluorescent ubiquitination-based cell cycle indicator. We found that the cells that initiate invasions are preferentially quiescent, whereas cell proliferation is associated with the extension of invasions. These data suggest that matrix degradation and cell proliferation are coupled during the invasion and escape of human breast cancer cells and highlight the critical role of matrix proteolysis in governing tumor phenotype.

scholarly journals Dovitinib Triggers Apoptosis and Autophagic Cell Death by Targeting SHP-1/p-STAT3 Signaling in Human Breast Cancers

2019 ◽  
Vol 2019 ◽  
pp. 1-14 ◽  
Author(s):  
Yi-Han Chiu ◽  
Yi-Yen Lee ◽  
Kuo-Chin Huang ◽  
Cheng-Chi Liu ◽  
Chen-Si Lin
Keyword(s):  
Breast Cancer ◽  
Cell Death ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Ectopic Expression ◽  
Health Concern ◽  
Breast Cancer Cell Lines ◽  
Breast Cancers ◽  
Human Breast ◽  
Stat3 Inhibition

Breast cancer is the most common cancer and the leading cause of cancer deaths in women worldwide. The rising incidence rate and female mortality make it a significant public health concern in recent years. Dovitinib is a novel multitarget receptor tyrosine kinase inhibitor, which has been enrolled in several clinical trials in different cancers. However, its antitumor efficacy has not been well determined in breast cancers. Our results demonstrated that dovitinib showed significant antitumor activity in human breast cancer cell lines with dose- and time-dependent manners. Downregulation of phosphor-(p)-STAT3 and its subsequent effectors Mcl-1 and cyclin D1 was responsible for this drug effect. Ectopic expression of STAT3 rescued the breast cancer cells from cell apoptosis induced by dovitinib. Moreover, SHP-1 inhibitor reversed the downregulation of p-STAT3 induced by dovitinib, indicating that SHP-1 mediated the STAT3 inhibition effect of dovitinib. In addition to apoptosis, we found for the first time that dovitinib also activated autophagy to promote cell death in breast cancer cells. In conclusion, dovitinib induced both apoptosis and autophagy to block the growth of breast cancer cells by regulating the SHP-1-dependent STAT3 inhibition.

Imatinib Mesylate (Gleevec)

Top Drugs ◽  
2015 ◽  
Author(s):  
Jie Jack Li
Keyword(s):  
Breast Cancer ◽  
Side Effects ◽  
Cancer Cells ◽  
Childhood Leukemia ◽  
Kinase Inhibitors ◽  
Protein Kinase Inhibitors ◽  
Follicle Cells ◽  
Type I ◽  
Breast Cancers ◽  
Normal Cells

Great strides had been made in the war against cancer with chemotherapy even before the emergence of protein kinase inhibitors. For instance, prior to vinblastine (1, Velban) became available in 1964 for the treatment of lymphoma, the diagnosis of Hodgkin’s disease (a cancer of the lymph nodes) was virtually a death sentence. Today there is a 90% chance of survival with the treatment by vinca alkaloids such as 1 and other chemotherapies. Similarly, when Sidney Farber discovered the effects of methotrexate (2, Trexall) on leukemia, it marked the beginning of the triumph over childhood leukemia. Following Barnett Rosenberg’s discovery of cisplatin (3, Platinol)’s effects on tumor cells in 1967, cisplatin and its analogs such as carboplatin (4, Paraplatin) and oxaliplatin (5, Eloxatin) contributed significantly in boosting the survival rate of patients with metastatic testicular cancer, ovarian tumors, and bladder cancer. Most significantly, breast cancer, a malady striking one in eight women, has been effectively managed via a plethora of treatments including surgery, radiation, and chemotherapies. The arsenal of chemotherapeutics for treating breast cancer includes SERMs such as tamoxifen (6) and raloxifene (7, Evista). Type I, II, and III aromatase inhibitors have now also been widely prescribed to combat breast cancers (more details may be found in chap. 4). Today, breast cancer is sometimes viewed as a chronic disease that can be managed, rather than a lethal disease. Despite the efficacy of the aforementioned chemotherapeutics, they kill cancer cells and normal cells with equal ferocity. (Some have compared chemotherapy to a “carpet bombing” strategy.) However, the reason these chemotherapies are effective is that cancer cells divide at much faster rate than normal cells; therefore, chemotherapies kill more malignant cells than healthy cells. Chemotherapies invariably come with significant side effects rooted. For example, hair follicle cells have a physiologically high mitosis rate; therefore, chemotherapies kill them faster than other healthy cells. In the same vein, other common side effects of chemotherapy include diarrhea (because ephithelial renewal is inhibited), bone marrow suppression (because granulopoiesis, thrombopoiesis, cytopoiesis, and erythropoiesis are inhibited), and lymph node damage (because of lymphocyte multiplication inhibition causes immune weakness).

Pleiotrophin Secreted from Human Breast Cancer MCF-7-Ptn Cells Activates Stromal Fibroblasts, Induces Epithelial Island Formation, and Remodels the Microenvironment.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2568-2568 ◽  
Author(s):  
Masahiko Zuka ◽  
Yunchao Chang ◽  
Zhaoyi Wang ◽  
James R. Berenson ◽  
Thomas F. Deuel
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Human Breast Cancer ◽  
Breast Cancer Cells ◽  
Breast Cancers ◽  
Human Breast ◽  
Nih3t3 Cells ◽  
Inappropriate Expression ◽  
Nih 3T3 ◽  
Mcf 7

Abstract Pleiotrophin (PTN, Ptn) is an 18 kD cytokine that is expressed in many human breast cancers and its gene is inappropriately expressed in cell lines derived from these breast cancers. To study the siginificance of inappropriate expression of Ptn in human breast cancer cells on surrounding stromal cells, we first compared nude mouse xenografts of MCF-7 and MCF-7-Ptn cells. MCF-7-Ptn cells lack the Receptor Protein Tyrosine Phosphatase (RPTP)b/z, the PTN receptor, and thus are not responsive to PTN through autocrine or paracrine stimulation. The MCF-7-Ptn cell xenografts grew rapidly whereas MCF-7 cells xenografts were barely detectable 6 weeks after injection. MCF-7-Ptn cells that were co-injected with equal numbers of NIH3T3 cells grew even more rapidly in the flanks of the nude mice. Surprisingly, the MCF-7-Ptn cell explants developed a morphological phenotype remarkably similar to that of the human invasive ductal carcinoma. We then co-cultured MCF-7 cells that express Ptn (MCF-7-Ptn cells) with NIH 3T3 cells. Secretion of PTN from MCF-7-Ptn cells induced formation of sharply defined clusters of MCF-7-Ptn cells, termed “epithelial islands”, that were surrounded by dense fibrous bands interspersed with NIH 3T3 cells that morphologically closely resemble carcinoma associated fibroblasts (CAFs). A striking increase in tropoelastin and expression of type IV procollagen mRNA was identified in NIH3T3 cells co-cultured with MCF-7-Ptn cells. Furthermore, different markers often resulting from stromal cell-carcinoma cell interactions in breast cancer, including protein kinase C (PKC)-d, and both human and murine matrix metalloproteinase (MMP) 9 were identified either in cells or in the culture media taken from MCF-7-Ptn/NIH3T3 cell co-cultures. The induction of these biochemical and morphological features in the co-cultures of MCF-7-Ptn and NIH3T3 cells was demonstrated to be Ptn expression dependent, PTN-secretion dependent, and NIH3T3 cell dependent. The data suggest that PTN secretion alone from human breast cancer cells with inappropriate expression of Ptn is sufficient to markedly remodel the microenvironment of the breast cancer cell and induce a morphological transition of the MCF-7-Ptn cells and NIH3T3 cells to patterns resembling breast carcinomas through activation of the PTN/RPTPb/z signaling pathway in NIH3T3 cells and reciprocal signaling between the carcinoma stromal cells and the PTN secreting breast cancer cells.

A less invasive method for orthotopic injection of breast cancer cells into the mouse mammary gland

2016 ◽  
Vol 51 (1) ◽  
pp. 85-88 ◽  
Author(s):  
Luz E Tavera-Mendoza ◽  
Myles Brown
Keyword(s):  
Breast Cancer ◽  
Mammary Gland ◽  
Cancer Cells ◽  
Cancer Biology ◽  
Mouse Mammary Gland ◽  
Breast Cancers ◽  
Biologically Relevant ◽  
Therapeutic Development ◽  
Invasive Method ◽  
Animal Handling

Breast cancer is the most common type of cancer diagnosed in women, and the second most common cause of cancer-related deaths in women in North America. The use of laboratory mice in research is an essential tool for the study of breast cancer biology and for pre-clinical therapeutic development. While subcutaneous flank injections of cancer cells are widely used for studying breast cancer biology and for exploring novel therapies, orthotopic xenografting of tumors into the mouse mammary gland allow for the study of breast cancers in a biologically relevant microenvironment. In this study we report a modification of the method of orthotopic injections of cancer cells into the mouse mammary gland which greatly reduces the effects of surgery in mice including decreased wound size, procedure time and anesthesia. It also removes the risk of accidentally puncturing the peritoneal cavity. Consequently post-operative animal handling and stress are significantly reduced. All of these advantages are present without compromising procedure success rate. Therefore, this modification makes orthotopic mammary gland injection a more efficient procedure and greatly improves animal welfare.

How to target estrogen receptor-negative breast cancer?

2003 ◽  
pp. 261-266 ◽  
Author(s):  
H Rochefort ◽  
M Glondu ◽  
M E Sahla ◽  
N Platet ◽  
M Garcia
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Cancer Cells ◽  
Targeted Therapies ◽  
Cathepsin D ◽  
Human Breast Cancer ◽  
Breast Cancers ◽  
Human Breast

Estrogen receptor (ER)-positive breast cancers generally have a better prognosis and are often responsive to anti-estrogen therapy, which is the first example of a successful therapy targeted on a specific protein, the ER. Unfortunately ER-negative breast cancers are more aggressive and unresponsive to anti-estrogens. Other targeted therapies are thus urgently needed, based on breast cancer oncogene inhibition or suppressor gene activation as far as molecular studies have demonstrated the alteration of expression, or structure of these genes in human breast cancer. Using the MDA-MB.231 human breast cancer cell line as a model of ER-negative breast cancers, we are investigating two of these approaches in our laboratory. Our first approach was to transfect the ER or various ER-deleted variants into an ER-negative cell line in an attempt to recover anti-estrogen responsiveness. The unliganded receptor, and surprisingly estradiol, were both found to inhibit tumor growth and invasiveness in vitro and in vivo. The mechanisms of these inhibitions in ER-negative cancer cells are being studied, in an attempt to target the ER sequence responsible for such inhibition in these cancer cells. Another strategy is trying to inhibit the activity or expression of an oncogene specifically overexpressed in most breast cancers. This approach was recently shown by others to be efficient in breast cancer therapy with HER2-Neu oncogene amplification using Herceptin. Without excluding other molecular putative targets, we have focused our research on cathepsin D as a potential target, since it is often overexpressed in aggressive human breast cancers, including ER-negative tumors, and rarely associated with HER2-Neu amplification. Our first results obtained in vitro on cell lines and in vivo in tumor xenografts in nude mice, illustrate that the mode of action of cathepsin D in breast cancer is useful to guide the development of these therapies. In the past 20 years we have learned that the action of cathepsin D is complex and involves both intracellular and extracellular activities due to its proteolytic activity and to interactions with membrane components without catalytic activity. Each of these mechanisms could be potentially inhibited in an attempt to prevent tumor growth. Breast cancer is a very heterogeneous and multigenic disease and different targeted therapies adapted to each category of breast cancer are therefore required. Validated assays in the primary tumor of molecular markers such as ER, HER2-Neu and cathepsin D should help to predict which targeted therapy should be applied to cure breast cancer patients.

Type I IGF receptor and acquired tamoxifen resistance in oestrogen-responsive human breast cancer cells

1993 ◽  
Vol 29 (16) ◽  
pp. 2256-2264 ◽  
Author(s):  
Lynda R. Wiseman ◽  
Michael D. Johnson ◽  
Alan E. Wakeling ◽  
Anne E. Lykkesfeldt ◽  
Felicity E.B. May ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Human Breast Cancer ◽  
Breast Cancer Cells ◽  
Tamoxifen Resistance ◽  
Type I ◽  
Human Breast Cancer Cells ◽  
Human Breast ◽  
Type I Igf Receptor ◽  
Igf Receptor

scholarly journals Inhibition of estrogen receptor signaling

2005 ◽  
Vol 8 (3) ◽  
Author(s):  
E. M. Rosen ◽  
S. Fan
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Estrogen Receptor Alpha ◽  
Dietary Factors ◽  
Type I ◽  
Breast Cancers ◽  
Human Breast ◽  
Estrogen Receptor Signaling ◽  
Reduce Breast Cancer Risk ◽  
Pharmacologic Agents

The estrogen receptor-alpha (ER-α) is a Type I nuclear receptor that is over-expressed in the majority of human breast cancers and plays a significant role in the development and progression of these cancers. As estrogen plays important roles in the etiology of breast cancer and the growth of established ER-α expressing cancers, intense interest has been generated in understanding the mechanisms by which ER-α signaling is regulated physiologically and using this knowledge to develop interventions to inhibit ER-α signaling. These efforts have met with some success in the development of pharmacologic agents that can reduce breast cancer risk, prevent recurrence of established cancers, and treat advanced cancers with considerably less side effects than cytotoxic chemotherapy. Here, we will review some of the mechanisms that operate to inhibit ER-α signaling and describe how pharmacologic agents and dietary factors interact with ER-α to block its activity. In the process of reviewing these mechanisms, we will highlight their clinical implications.

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