Breast Cancer

Cancer Control

Drug Discovery & Development

Environmental Health Science

Proteases & Metastasis

Molecular Oncology & Human Genetics

The Breast Cancer Research Program has been an established focus of investigation in the BAKCI for more than 30 years. This program integrates basic breast cancer biology with clinical programs in early detection and prevention.

Scientists at the BAKCI established the first, long-term breast cancer cell line, known as MCF-7, in the 1970’s. This line has been distributed all over the world and is used in basic studies on, for example, the endocrine control of breast cancer, as well as in work directed toward development of new anticancer drugs.

Currently within the program there are laboratories involved in a wide variety of basic and clinical studies. Newly established laboratories are carrying out molecular, genetic and cytogenetic characterizatins of both human and experimental cancers. Special emphasis is placed on research into the early events in breast cancer development and in experimental systems for studying preneoplastic events. A recent advance is the development of a human breast epithelial line, known as MCF10AT, that grows in nude beige mice and mimics the histological picture of proliferative breast disease seen in women at high risk of developing breast cancer. These proliferative lesions develop into carcinoma upon prolonged growth in the mice. Administration of estrogen accelerates the process. Other laboratories are concerned with the later stage processes in breast cancer — the factors that influence metastasis as well as the emergence of hormone independence and drug resistance. An additional theme is the role of the host in mammary tumor development and in metastasis, both on the level of tissue interactions between mammary epithelium and stroma, as well as inflammatory and immune response effects.

Basic studies on the biology of breast cancer are complemented by several large clinical resources. The BAKCI maintains a repository of tissues and serum from more than 1,200 breast cancer patients whose clinical course is being closely monitored. Wayne State University and Harper Hospital have established a Breast Cancer Prevention Clinic in which women at high risk of developing breast cancer participate in a variety of studies aimed, ultimately, at early detection and prevention of the disease. The BAKCI houses the Walt Comprehensive Breast Center which combines mammography, physical examination and health education approaches to early detection. Each of these resources offer opportunities for a wide variety of research into breast cancer problems be they at the basic, clinical or cancer control levels.

The Cancer Control Program focuses on etiology of cancers affecting the population of metropolitan Detroit. Growing emphasis is placed on translational research, integrating basic laboratory methods into epidemiologically designed studies. The faculty of the Cancer Control Program compliment their research with that of members of other Cancer Center Programs in a continuing attempt to identify the biologic and genetic basis of cancer onset, and the validation of biological markers through their use in human epidemiologic studies. Faculty of the Cancer Control Program have doctoral training not only in epidemiology, but in biostatistics, anthropology, mathematics and clinical medicine.

The backbone of the Cancer Control Program is the Metropolitan Detroit Cancer Suveillance System, a National Cancer Institute SEER Cancer Registry. This registry identifies approximately 22,000 new cancer cases yearly and has accumulated cancer incidence data for more than 28 years. This data set provides outstanding opportunities for the development of case-control studies, particularly those emphasizing an urban industrial population.

The Cancer Control Program has focused its research activities in three general areas: ethnic variation in cancer; occupational and environmental exposures in cancer etiology; and causes of breast cancer. The Detroit area provides an optimal mix of socioeconomic characteristics to undertake studies exploring issues of urban residence, industrial employment and ethnic characteristics.

The Cancer Control Program addresses not only issues pertaining to original research, but also to practical application of knowledge of cancer patterns in the community. Through the SEER cancer registry, the cancer control program is strategically placed to apply knowledge of cancer trends to the benefit of community members and organizations.

A. Drug Discovery
The Drug Discovery segment of the program focuses on the identification of agents that selectively target solid tumors of common occurrence using molecular, cellular, and implanted tumor models. The primary thrust of the program involves identifying and testing new agents, enhancing the effects of standard agents, and developing new approaches to discovering new modalities. Over the past few years an average of 5,000 - 8,000 synthetic chemicals and natural product extracts have been screened for potential anticancer activity. The initial screening emphasis is against tumors of breast, colon, lung, pancreas and prostate since these tumor types are responsible for approximately 70% of the cancer mortality in the United States. Follow up therapeutic trials in animals identify agents that offer therapeutic advantages compared with traditional drugs.


B. Preclinical Drug Development
The foci of the preclinical development segment are mechanistic studies on novel agents, new targets, innovative drug delivery systems and drug resistance. The objective is to use laboratory derived data to define fundamental information needed to develop more efficacious clinical therapies against solid human tumors. Preclinical drug development is managed by pharmacologists specializing in pharmacodynamics and pharmacokinetics of anticancer therapies. The pharmacology group serves as a bridge between basic research and clinical investigation, providing basic pharmacology information, mechanistic detail and analytical chemistry and technical support to a number of clinical projects related to anticancer chemotherapy, and developing new analytical systems to be used at both the clinical and preclinical levels. The pharmacology unit serves as the principal vehicle for translating scientific breakthroughs into new anti-cancer treatments. In addition, investigators analyze tumor and blood specimens taken from patients for assessment of pharmacologic activity. The translational theme is a critical element in the program enabling harmonization between basic and clinical scientists. Two important translational research projects underway are designed to streamline the flow of new drugs to clinical trial and to enable the trials to be conducted in an efficient manner. The two projects involve myelotoxicity in vitro as a means of predicting clinical outcomes and modeling of human drug metabolism to understand potential drug/drug interactions. Both projects are designed to utilize investigational pharmacology experiments to efficiently design and monitor progress of the clinical studies.

C. Clinical Development
With its main focus on pharmacological (therapeutic) assessment, the Phase I clinical trials unit studies the clinical characteristics of a drug by designing a therapeutic program from the point of view of patient dosing and administration schedule. Carefully controlled Phase I clinical trials of new anticancer agents are employed to determine the maximum tolerated dose, the dose-limiting toxicity, and other toxicities associated with drug administration in adult patients, emphasizing women and minority patients. Whenever possible, an accelerated titration dose-escalation trial design is considered based on translating pharmacology and toxicology data from preclinical species to man.

The Institute of Environmental Health Sciences (www.iehs.wayne.edu) occupies approximately 33,000 square feet of laboratory space in MCHT, located at 2727 Second Ave. It has twelve full-time faculty, four of whom are members of the Graduate Program in Cancer Biology. Faculty research programs focus on examining the molecular and cellular mechanisms by which environmental factors induce cell injury, and alter cell signaling, cell growth and differentiation. Areas of concentrated interest include studies which focus on intracellular signaling pathways involving orphan receptors, protein kinases and phosphatases; molecular regulation of enzymes involved in xenobiotic biotransformation; signaling pathways involved in the regulation of cell function; regulation and function of the aryl hydrocarbon (Ah) receptor; signaling pathways and components involved in the cell cycle and apoptosis; cell and organ damage associated with oxidative stress; genomics, and the role of DNA repair enzymes in cancer etiology and progression. Contemporary high through-put technologies, including microarray analysis, chip-based proteomics, computational biology (i.e. bioinformatics) and transgenic animals, in conjunction with cellular, molecular, and biochemical approaches are being employed in these NIH-funded research programs. The Institute of Environmental Health Sciences is the headquarters of the Environmental Health Science Center in Molecular and Cellular Toxicology with Human Applications.

Metastasis is the dynamic and interactive processes by which cancer cells migrate locally or distally from a primary tumor. The blood stream is the ultimate route for dissemination of most metastases and the interactions of cancer cells with circulating host cells including the vascular endothelium plays a pivotal role in the metastatic cascade and overall progression of tumors. The malignancy of cancer cells cannot be determined by any single parameter, but is probably represented by a sum of many phenotypic characteristics such as surface receptors and proteolytic enzymes, some of which are transiently expressed. Each of these phenotypic characteristics may not be of equal importance as cancer cells may use several strategies to achieve the same result. Similarly, a number of therapeutic strategies may be utilized to interrupt tumor progression and the dissemination, growth and invasion of metastatic lesions.

The research of the members of the Protease and Metastasis Program spans virtually every facet of this complex interplay between cancer cells and the host. The expression of certain oncogenes may result in the elaboration of phenotypic characteristics conducive to tumor cell metastasis. The interaction of cancer cells with host normal cells and matrix is mediated by cell surface integrin receptors, cadherins, and lectins which modulate tumor cell adhesion. This is an area of study within the program, as is the mechanism(s) of transmembrane signaling and gene expression which occurs during tumor cell-normal cell and tumor cell matrix interaction. Following transmembrane signaling, an important link between the external stimulus and the cancer cell response is the cytoskeleton which is also another active area under study. The modulation of these events by eicosinoids and related bioactive lipids,through their effects on specific kinases and phosphatases and phosphorylation/dephosphorylation of key intracellular proteins, is an active area of study within the program.

Tumor cells are known to interact with elements of the hemostatic system during metastasis, therefore, an active group within the program is studying tumor procoagulant proteins and the role of platelets in metastasis. Following tumor cell arrest, degradation of the subendothelial matrix is a necessary prerequisite to the processes by which tumor cells exit from the vasculature. Cancer cell proteases and protease inhibitors, which may be important in this aspect of cancer cell invasion, are a long established interest of members of this program.

Several members have interests related to the targeting of specific therapies which may modulate in both a positive and a negative way, the process of tumor cell metastasis. Various effects of radiation and cytotoxic chemotherapy on the metastatic process are being studied, as well as the mechanism(s) of drug resistance with special emphasis on metastatic lesions. The metastatic process is being studied at all levels, including genetic, molecular, biochemical, cellular and organismal. In addition, there is an active synthetic program for the construction of lipid, peptide and other organic molecules which may inhibit various aspects of the metastatic process. A strong history of past and present collaboration among individuals of this group afford the opportunity for broad based training in many of the aspects and techniques of research on tumor/stromal interactions as they relate to tumor progression.

The Molecular Oncology Graduate Program was initiated in 1989 as a focus of investigation in the BAKCI. Its goal is to integrate the powerful concepts and techniques of molecular biology with other approaches to investigation, diagnosis, treatment and prevention of cancer. It brings together molecular biologists, cell biologists, somatic cell geneticists, cytogeneticists, biochemists, endocrinologists, physiologists, pharmacologists, pathologists and clinical investigators.

Laboratories within the program carry out a wide range of studies on human and experimental cancers. Ongoing studies include the molecular mechanisms by which DNA damage, resulting in a mutation or chromosomal rearrangement, leads to cancer in specific cell types; molecular cytogenetic analysis using cloned molecular probes to identify microdeletions too small to see by standard or high resolution chromosome banding, and to locate specific chromosomal breakpoints in cancer cells; cloning these breakpoints in order to identify the gene or genes whose inactivation or activation is involved in specific types of carcinogenesis; isolation of specific human translocation or deletion chromosomes in hybrid cells on a rodent background to facilitate chromosome regional mapping and the reverse genetics needed to localize, clone and characterize new oncogenes or tumor suppressor genes. Other studies involve investigating at a molecular level the genes that influence hormone receptor activity or otherwise determine the extent of hormone dependence of endocrine cancers; the regulation of metabolic pathways involved in cell proliferation, for example, polyamine biosynthesis or biosynthesis of specific growth factors and their receptors. Studies involving the molecular analysis of DNA replication, repair and mutagenesis leading to cancer are being carried out. Still, other scientists are investigating the mechanisms of carcinogenesis by viruses such as papillomavirus, hepatitis B virus, retroviruses and papova viruses.

Another strength of this program is Cancer Genetics in which information emerging from the studies of the genomes of eukaryotes from yeast to man is being applied to the discovery new genes affecting "high risk" populations and the mechanisms which predispose them to cancer. Then, using this mechanistic information researchers are developing therapeutic approaches to prevent and cure cancer in these populations. Using a combination of in vitro cell systems and genetically engineered experimental animals, researchers are modeling therapeutics from a knowledge of mechanism of action of genes like p53 whose mutation in the germline predisposes to genomic instability. The inhibition of spontaneous genomic instability will be a target mechanism of this program through which the incidence of cancer will be reduced. Studies in human populations at extreme risk to cancer will then be applied to the general population in which the cancer risk is more subtle. A major focus of this program is the study of mechanisms of genomic instability and checkpoint control using cells lines and animal models. An integrated approach is being developed applying knowledge from yeast systems mechanisms, DNA repair and checkpoint control to study specific syndromes in which the homologous human genes are involved in cancer predisposition. Further studies will identify the human homologues of significant DNA repair and checkpoint genes so as to analyze their role in genetic penetrance and predisposition to cancer. This program integrates cell biology, yeast genetics, human genetics and genomics and mouse molecular genetics.