STAGES OF BREAST DEVELOPMENT: NORMAL TO METASTATIC DISEASE Release Date: September 2, 1999 PA NUMBER: PA-99-162 National Cancer Institute National Institute of Child Health and Human Development National Institute of Diabetes and Digestive and Kidney Diseases National Institute on Aging National Institute of Environmental Health Sciences THIS PA USES THE "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. IT INCLUDES DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS PA. PURPOSE The National Cancer Institute (NCI), National Institute of Child Health and Human Development (NICHD), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute on Aging (NIA), and National Institute of Environmental Health Sciences (NIEHS) invite investigator-initiated research grant applications to study the molecular, cellular, endocrine, and other physiological influences on the development and maturation of the normal mammary gland and alterations involved in early malignant and metastatic breast cancer. Multi-disciplinary collaborations, for example between cell biologists, molecular endocrinologists, bioengineers, geneticists, and mammary pathologists, are encouraged. Appropriate studies include, but are not limited to, documenting the role of dynamic hormonal influences and determining the role of cell growth, apoptosis, and differentiation in mammary gland maturation; integrating knowledge of cell signaling in breast tissue with whole organ biology; developing models of breast differentiation; and studies focusing on the characteristics of breast tumor physiology particularly in relation to metastasis. It is expected that a complete understanding of mammary gland development will form critical underpinnings for continued advances in detecting, preventing and treating breast cancer. This program announcement (PA) will expire in two years from the last receipt date in the calendar year. NIH Grants policies apply to these awards. HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," a PHS-led national activity for setting priority areas. This PA, Stages of Breast Development: Normal to Metastatic Disease, is related to the priority area of cancer. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No.017-001-00474-0 or Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202-512-1800), or at http://odphp.osophs.dhhs.gov/pubs/hp2000. ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign, for-profit and non-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State or local governments, and eligible agencies of the Federal government. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. MECHANISM OF SUPPORT This PA will use the National Institutes of Health (NIH) research project grant (R01). Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. The total project period for an application submitted in response to this PA may not exceed 5 years. Specific application instructions have been modified to reflect "MODULAR GRANT" and "JUST-IN-TIME" streamlining efforts being examined by the NIH. Complete and detailed instructions and information on Modular Grant applications can be found at http://grants.nih.gov/grants/funding/modular/modular.htm For budgets of $250,000 direct costs or less in all years, funds must be requested in $25,000 direct cost modules. A feature of the modular grant is that no escalation is provided for future years, and all anticipated expenses for all years of the project must be included within the number of modules being requested. Only limited budget information is required and any budget adjustments made by the Initial Review Group will be in modules of $25,000. Applications requesting more than $250,000 should follow the standard PHS 398 instructions. RESEARCH OBJECTIVES Background Breast cancer is the leading site of new cancer cases in women, and the second leading cause (after lung cancer) of cancer death among women. In 1998, an estimated 178,700 new cases of breast cancer were expected to be diagnosed, and 43,500 women were expected to die of this disease in the United States. Approximately two million women have been diagnosed with breast cancer at some point in their lives. Breast cancer also occurs among men, though far more rarely (approximately 1,600 new cases diagnosed in 1998); treatment for male breast cancer is guided by our understanding of the disease in women. The Breast Cancer Progress Review Group (BCPRG), comprised of basic and clinical researchers from academia, industry, and government, and representatives of the patient advocacy community, was established by the National Cancer Institute to help develop a national plan for breast cancer research during the next decade. The BCPRG assessed the status of basic, translational, and clinical breast cancer research and identified and prioritized the scientific research opportunities and needs that must be addressed to continue and accelerate progress in the prevention and treatment of breast cancer. The BCPRG Report is available at http://wwwosp.nci.nih.gov/planning/prg/bprgtableofcontents.htm. This Program Announcement is in response to several recommendations of the BCPRG regarding breast cancer biology and genetics. In particular the BCPRG identified several areas in which an increased knowledge base would greatly aid continued progress: (1) normal breast development, (2) the earliest breast lesions leading to invasive cancer, and (3) how breast cancer spreads throughout the body. In addition, it recognized our need for model systems that better mimic human breast disease, for greater access to human breast tissues and cell lines, and for greater collaboration among investigators from diverse disciplines. Research Scope and Goals National Cancer Institute (NCI) Our limited understanding of the biology and developmental genetics of the normal mammary gland has been a barrier to progress against breast cancer. Much of our biological research in breast cancer has focused on understanding the initiation and development of the disease. This research has been fruitful, but it is now clear that a more complete understanding of the normal mammary gland at each stage of development is needed if we are to make further significant gains. Mammary gland growth and maturation consist of a series of very highly ordered events involving interactions among a number of distinct cell types, regulated by complex interactions of many hormones including estrogens, androgens, progesterone, prolactin, in addition to numerous growth factors such as insulin- like growth factor-I (IGF-I) and parathyroid hormone related protein (PTHrP). Normal development, as well as pregnancy and lactation, all bring profound changes to the breast in response to the changing hormonal environment, e.g., morphological changes and a marked increase in epithelial growth with pregnancy, dramatic tissue remodeling and epithelial cell death after lactation, and repeated changes through the menstrual cycle. These events comprise the developmental course of a mammary gland. Mammary tumorigenesis is clearly influenced by the specific details of the developmental course as indicated by the risk factors associated with the disease, i.e., being female, nulliparity or first full-term pregnancy after age 30, and menarche before age 12. How these complex hormonal factors contribute to breast cancer, however, is poorly understood. Another major question in breast cancer biology is the nature of the mammary stem cell. Transplantation studies in model systems that regenerate a functional mammary gland suggest that stem cells exist throughout the mammary gland and at all stages of development. Studies also suggest that the cells that initiate mammary gland development and generate the secretory, lobuloalveolar structures are the targets of etiologic agents that cause breast cancer. The nature of these stem cells and the mechanisms by which the population expands and differentiates, however, still needs to be defined. Understanding these processes will likely shed light on the critical alterations that lead to transformation. It is also clear that a balance between cell proliferation, cell differentiation and cell death in the stem cell population and throughout the mammary gland is critical for normal development. In contrast, perturbations in this balance can contribute to cancer development. Conditions of up-regulated cell proliferation or down-regulated apoptosis can allow accumulation of mutations that contribute to the subsequent development of breast cancer. It is not clear, however, how normal mechanisms controlling growth stimulation and cell death in the human breast act in tumor development, in protection from tumor development, or in the dissemination of the disease. Finally, breast developmental biology has been limited largely to the study of the rat and mouse with studies in human gland development significantly lagging. Better model systems for human premalignant breast disease and breast cancer (animal models, human mammary cells, and organ culture) are needed to understand the human disease and answer the questions above. Such models will help identify genetic components for breast cancer, identify biological markers that can evaluate preventive and therapeutic agents, and test potential new agents for prevention and treatment. The following are examples of key scientific questions and opportunities identified by the NCI Breast Cancer Progress Review Group: Normal Biology of the Mammary Gland 1. What is the nature of mammary gland stem cells? 2. What are the principal cell types involved in mammary development, and what are the mechanisms of their interaction? 3. What is the effect and mechanism of temporal hormonal expression in mammary development. 4. How are growth, death, and differentiation controlled in mammary development? 5. What steroid receptors coactivators/corepressors and other transcriptional regulatory mechanisms are critical in mammary development? 6. What are the principal signaling molecules and pathways in mammary gland development? 7. What are the principal cell cycle checkpoints and their controls in mammary development? 8. What genes are involved in normal breast development? 9. What role do epithelial-stromal interactions play in normal breast biology? 10. Exploit transgenic mouse and other models, and cell and organ cultures derived from them, to study the stages of normal mammary development. Early Malignant Biology of the Mammary Gland 1. What is the exact nature of the earliest genetic steps in breast cancer in both human and mouse tumors? 2. What defines breast epithelium at risk for cancer. 3. Which hormonal, growth factor, and adhesion signals are critical in early malignancy? 4. What is the role of interactions between the extracellular matrix and stromal cells in epithelial transformation? 5. Exploit transgenic mouse and other models to study early mammary tumor development. Breast Cancer Metastasis 1. What are the exact mechanisms whereby breast cancer begins to invade the local area of the breast? 2. What is the role of stromal influences in the metastatic process for breast cancer? 3. How is the bone response to skeletal metastasis by breast cancer cells controlled? 4. What mechanisms allow survival of disseminated breast tumor cells in distant sites? 5. How is tumor angiogenesis in breast cancer regulated? 6. What mechanisms lead to the refractory nature of metastatic breast cells toward systemic treatment? 7. Exploit transgenic mouse and other models to the specific study of breast cancer metastasis. National Institute of Child Health and Human Development (NICHD) NICHD supports research in the area of childhood growth and development. Of particular interest is research that focuses on the developmental processes regulating the pubertal growth phase of mammary gland development. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) NIDDK, through its Endocrinology and Growth Factors research programs, has focused on fundamental questions about both organogenesis and mature cell function, including: (1) the roles of cell and tissue-specific signals (e.g. sonic hedgehog, BMPs, wnts) in the determination of cell fate during development; (2) the role(s) of steroid hormones, including the roles of nuclear receptor structure in ligand binding, the effects of SERMs in mediating receptor function, determinants of tissue-specific action, interaction with nuclear accessory proteins (e.g. co-activators and co-repressors) in the regulation of gene expression, and signaling cross-talk with other nuclear or cell surface receptors, and (3) the role(s) of hormones and growth factors in mediating normal breast development and the role(s) such signaling may play in development of disease. National Institute on Aging (NIA) The mission of the NIA is to support and conduct research on the aging process, age-related diseases, and special problems and needs of the aged. Thus, the NIA invites research applications focused on genetic, molecular and cellular mechanisms underlying age-related changes in normal and neoplastic breast tissue to hormonal and other bioregulatory systemic and paracrine factors, leading to initiation, progression and metastasis of breast cancer in middle-aged and older people. National Institute of Environmental Health Sciences (NIEHS) The NIEHS mission includes the support of research investigating the effects of chemical, physical and biological environmental agents on human health and well- being. A significant number of human diseases come about as a result of interactions between genetic factors and exposure to environmental factors over time associated periods of aging. The major goal of the NIEHS is to develop knowledge that will permit the better management of risks associated with living in a world that includes exposures to environmental agents that induce adverse health effects. The NIEHS is interested in receiving investigator-initiated research grant applications to examine the role and mechanism of action of chemical, physical or biological environmental agents that adversely modify cellular, molecular, and/or physiological events associated with the growth and development of the normal, aging, and neoplastic mammary gland. In particular, studies which focus on critical windows for exposures during different periods of sexual development (i.e., in utero, childhood, puberty, pregnancy, lactation and menopause) are encouraged. Such studies would elucidate and delineate intervention principles for the prevention of environmentally-related disease as well as for protective actions by regulatory agencies. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their subpopulations must be included in all NIH supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification is provided that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing research involving human subjects should follow the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research", which have been published in the Federal Register of March 28, 1994 (FR 59 14508-14513), and in the NIH Guide for Grants and Contracts of March 18, 1994, Volume 23, Number 11, available on the web at the following URL address: http://grants.nih.gov/grants/guide/notice-files/not94-100.html INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of NIH that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are clear and compelling reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines on the Inclusion of Children as Participants in Research Involving Human Subjects" that was published in the NIH Guide for Grants and Contracts, March 6, 1998, and is available at the following URL address: http://grants.nih.gov/grants/funding/children/children.htm APPLICATION PROCEDURES The modular grant concept establishes specific modules in which direct costs may be requested as well as a maximum level for requested budgets. Only limited budgetary information is required under this approach. The just-in-time concept allows applicants to submit certain information only when there is a possibility for an award. It is anticipated that these changes will reduce the administrative burden for the applicants, reviewers and Institute staff. The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants, with the modifications noted below. Applications kits are available at most institutional offices of sponsored research and may be obtained from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/435-0714, email: grantsinfo@nih.gov. For those applicants with internet access, the 398 kit may be found at: http://grants.nih.gov/grants/funding/phs398/forms_toc.html. The application will be accepted at the standard application deadlines for R01 as indicated in the application kit. Applicants are strongly encouraged to contact the program contacts listed under INQUIRIES with any questions regarding their proposed project and the goals of this PA. BUDGET INSTRUCTIONS Modular Grant applications will request direct costs in $25,000 modules, up to a total direct cost request of $250,000 per year. Applications that request more than $250,000 direct costs in any year must follow the traditional PHS 398 application instructions. The total direct costs must be requested in accordance with the program guidelines and the modifications made to the standard PHS 398 application instructions described below: o FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs (in $25,000 increments) and Total Costs [Modular Total Direct plus Facilities and Administrative (F&A) costs] for the initial budget period. Items 8a and 8b should be completed indicating the Direct and Total Costs for the entire proposed period of support. o DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD - Do not complete Form Page 4 of the PHS 398. It is not required and will not be accepted with the application. o BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT - Do not complete the categorical budget table on Form Page 5 of the PHS 398. It is not required and will not be accepted with the application. o NARRATIVE BUDGET JUSTIFICATION - Prepare a Modular Grant Budget Narrative page (see http://grants.nih.gov/grants/funding/modular/modular.htm for sample pages). At the top of the page, enter the total direct costs requested for each year. This is not a form page. o Under Personnel, list key project personnel, including their names, percent of effort, and roles on the project. No individual salary information should be provided. However, the applicant should use the NIH appropriation language salary cap and the NIH policy for graduate student compensation in developing the budget request. For Consortium/Contractual costs, provide an estimate of total costs (direct plus facilities and administrative) for each year, each rounded to the nearest $1,000. List the individuals/organizations with whom consortium or contractual arrangements have been made, the percent effort of key personnel, and the role on the project. Indicate whether the collaborating institution is domestic or foreign. The total cost for a consortium/contractual arrangement is included in the overall requested modular direct cost amount. Include the Letter of Intent to establish a consortium. Provide an additional narrative budget justification for any variation in the number of modules requested. o BIOGRAPHICAL SKETCH - The Biographical Sketch provides information used by reviewers in the assessment of each individual's qualifications for a specific role in the proposed project, as well as to evaluate the overall qualifications of the research team. A biographical sketch is required for all key personnel, following the instructions below. No more than three pages may be used for each person. A sample biographical sketch may be viewed at: http://grants.nih.gov/grants/funding/modular/modular.htm - Complete the educational block at the top of the form page; - List position(s) and any honors; - Provide information, including overall goals and responsibilities, on research projects ongoing or completed during the last three years; - List selected peer-reviewed publications, with full citations. o CHECKLIST - This page should be completed and submitted with the application. If the F&A rate agreement has been established, indicate the type of agreement and the date. All appropriate exclusions must be applied in the calculation of the F&A costs for the initial budget period and all future budget years. The applicant should provide the name and phone number of the individual to contact concerning fiscal and administrative issues if additional information is necessary following the initial review. Applications not conforming to these guidelines will be considered unresponsive to this PA and will be returned without further review. The PA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. Submit a signed, typewritten original of the application, including the checklist, and five signed, exact, single-sided photocopies, in one package to: CENTER FOR SCIENTIFIC REVIEW NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710 BETHESDA, MD 20892-7710 BETHESDA, MD 20817 (for express/courier service) REVIEW CONSIDERATIONS Applications will be assigned on the basis of established PHS referral guidelines. Applications that are complete will be evaluated for scientific and technical merit by an appropriate peer review group convened in accordance with NIH peer review procedures. As part of the initial merit review, all applications will receive a written critique and undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of applications under review, will be discussed, assigned a priority score, and receive a second level review by the appropriate national advisory council or board. Review Criteria The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. The reviewers will comment on the following aspects of the application in their written critiques in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered by the reviewers in assigning the overall score weighting them as appropriate for each application. Note that the application does not need to be strong in all categories to be judged likely to have a major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. Significance: Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? Approach: Are the conceptual framework, design, methods, and analyzes adequately developed, well-integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? Innovation: Does the project employ novel concepts, approaches or method? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? Investigator: is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if any)? Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? The initial review group will also examine: the adequacy of plans to include both genders, minorities and their subgroups, and children as appropriate for the scientific goals of the research and plans for the recruitment and retention of subjects; the provisions for the protection of human and animal subjects; and the safety of the research environment. AWARD CRITERIA Applications will compete for available funds with all other recommended applications. The following will be considered in making funding decisions: scientific merit of the proposed project as determined by peer review, availability of funds, program priority and responsiveness to the recommendations set forth in the BCPRG report. INQUIRIES Inquiries concerning this PA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Barbara A Spalholz, Ph.D. Division of Cancer Biology National Cancer Institute Executive Plaza North, Room 505 Bethesda, MD 20892-7385 Telephone: (301) 496-7028 FAX: (301) 402-1037 Email: bs62d@nih.gov Karen Winer, Ph.D. Endocrinology, Nutrition and Growth Branch National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 4B11 Bethesda, MD 20892- 7510 Telephone: (301) 435-6877 FAX: (301) 480-9791 Email: winerk@exchange.nih.gov Ronald N. Margolis, Ph.D. Senior Advisor, Molecular Endocrinology National Institute of Diabetes and Digestive and Kidney Diseases Natcher Building, Room 5AN-12J Bethesda, MD 20892-6600 Telephone: (301) 594-8819 FAX: (301) 435-6047 Email: rm76f@nih.gov Frank Bellino, Ph.D. Biology of Aging Program National Institute on Aging Gateway Building, Suite 2C231 Bethesda, MD 20892-9205 Telephone: (301) 496-6402 FAX: (301) 402-0010 Email: fb12a@nih.gov Gwen W. Collman, Ph.D. Division of Extramural Research and Training National Institute of Environmental Health Sciences P.O. Box 12233 Research Triangle Park, NC 27709 Telephone: (919) 541-4980 FAX: (919) 541-4937 Email: collman@niehs.nih.gov Direct inquiries regarding fiscal matters to: Mr. Bill Wells Grants Administration Branch National Cancer Institute Executive Plaza South, Room 243 Bethesda, MD 20892 Telephone: (301) 496-8796 FAX: (301) 496-8601 Email: ww14j@nih.gov Mr. Douglas E. Shawver Grants Management Branch National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 8A17F Bethesda, MD 20892 Telephone: (301) 496-1303 FAX: (301) 496-0915 Email: shawverd@exchange.nih.gov Charlette Kenley Grants Management Branch National Institute of Diabetes and Digestive and Kidney Diseases Natcher Building, Room 6AS-49D Bethesda, MD 20892-6600 Telephone: (301) 594-8847 FAX: (301) 480-3504 Email: kenleyc@extra.niddk.nih.gov Mr. Bob Pike Grants Management Office National Institute on Aging Gateway Building, Suite 2N212 Bethesda, MD 20892-9205 Telephone: (301) 496-1472 FAX: (301) 402-3672 Email: pikeb@exmur.nia.nih.gov David L. Mineo Division of Extramural Research and Training National Institute of Environmental Health Sciences P.O. Box 12233 Research Triangle Park, NC 27709 Telephone: (919) 541-1373 FAX: (919) 541-2860 Email: mineo@niehs.nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance, No. 93.396, 93.113, 93.847, 93.865, and 93.866. Awards are made under authorization of the Sections 301 and 405 of the Public Health Service Act amended (42 USC 241 and 284) and administered under NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or a Health Systems Agency Review. The PHS strongly encourages all grant and contract recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.
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