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



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

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.


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


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.


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

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



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  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

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

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
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
7. What are the principal cell cycle checkpoints and their controls in mammary
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
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

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
3. How is the bone response to skeletal metastasis by breast cancer cells
4. What mechanisms allow survival of disseminated breast tumor cells in distant
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

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

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.


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:


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:


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 301/710-0267,
email:  For those applicants with internet access, the 398
kit may be found at: 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.


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.

of the PHS 398.  It is not required and will not be accepted with 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 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

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:

- 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:

6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710
BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for express/courier service)


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

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.


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 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

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

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

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

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

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

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

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

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

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


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

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