GENETIC AND PHENOTYPIC MARKERS FOR IONIZING RADIATION-INDUCED BREASTCANCER IN RODENT AND HUMAN CELLS



NIH GUIDE, Volume 22, Number 26, July 15, 1994



PA NUMBER:  PA-94-080



P.T. 34



Keywords:

  0715036 

  Etiology 

  Nucleic Acids 

  Genetics 

  0765014 



National Cancer Institute



PURPOSE



The Division of Cancer Etiology of the National Cancer Institute (NCI)

invites grant applications from interested investigators through a

Program Announcement (PA) to study changes of gene expression that are

induced by exposure of pluripotent, or partially transformed, rodent

and human mammary epithelial cells to ionizing radiations; and to

define the role of such gene sequences in the progression to radiogenic

breast cancer in rodent models.  This initiative is in response to

Congressional language that NCI emphasize studies on the etiology of

female breast cancer as one of its top priorities.



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,

Genetic and Phenotypic Markers for Ionizing Radiation-Induced Breast

Cancer in Rodent and Human Cells, 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; Summary Report: Stock

No. 017-001-00473-1) through the Superintendent of Documents,

government Printing Office, Washington, DC 20402-9325 (telephone

202-783-3238).



ELIGIBILITY REQUIREMENTS



Applications may be submitted by domestic and foreign for-profit and

non-profit institutions, public and private, such as universities,

colleges, hospitals, laboratories, units of state or local governments,

and eligible agencies of the Federal government.  Applications from

minority individuals and women are encouraged.



MECHANISM OF SUPPORT



This PA is a one-time solicitation and will be supported through the

National Institutes of Health (NIH) traditional research project grant

(R01).  The applicant will have the sole responsibility for planning,

directing and executing the proposed research.  Because the nature and

scope of the research proposed in response to this PA may vary, it is

anticipated that the size of an award will vary also.



RESEARCH OBJECTIVES



Background



Young adult women and adolescent females under 20 years of age may be

unusually susceptible to ionizing radiation- induced breast cancer

(e.g., atomic bomb survivors, young female Hodgkin's lymphoma patients

treated by radiotherapy).  There also is evidence that young female

rodents show increased sensitivity to both chemical-induced and

radiation-induced mammary cancer.  Several lines of evidence, based

partly on the growth characteristics of cultured human breast carcinoma

cells and more strongly on experimental work on the induction of

mammary tumors in rodents, suggest that populations of precursor or

pluripotent stem-like cells that are prevalent during the formation and

differentiation of the mammalian female breast tissue are the main

targets for ionizing-radiation- induced genetic damage that eventually

may give rise to cancer.



Objectives



This PA encourages research applications to study the etiologic and

mechanistic basis for the apparent susceptibility of pluripotent cells

implanted into the developing breast tissue of rodents to undergo

malignant transformation by ionizing radiation.  It will focus on the

characterization and analyses of the genes and gene products that may

be differentially expressed during the progression of these precursor,

or partially transformed, rodent mammary epithelial cells into

malignant breast cancers.  Particular emphasis will be given to

defining the possible etiologic roles of such gene sequences in the

early stages of progression prior to malignancy (e.g., mutations that

result in increased dysplasia and loss of differentiation capabilities

in vivo; acquisition of growth factor and hormonal independence for

cellular proliferation in vitro).  Where feasible, comparative in vitro

or in vitro/in vivo studies of the effects of ionizing radiation on

non-malignant human mammary epithelial cells will be encouraged.

Because of the scope of the studies, involving both whole animals and

molecular and cellular endpoints, multidisciplinary applications are

encouraged.



The PA includes, but is not limited to:



o  A determination of the susceptibility and involvement of

precursor-like mammary epithelial cells in radiation-induced breast

cancer in the developing mammary tissue of young female rodents;



o  The isolation and subsequent genetic and biochemical analyses of

gene sequences and gene products that are differentially over- or

under-expressed during progression to radiogenic breast cancer in

rodent and, if feasible, in human breast epithelial cells;



o  The assessment, following radiation exposure, of differentially

expressed genes, proteins or mutations in breast epithelial precursor

cells to serve as biomarkers of preneoplastic lesions for

radiation-induced breast carcinomas in rodents and humans.



STUDY POPULATIONS



Special instructions to applicants regarding implementation of NIH

policies concerning inclusion of females and minorities in research

involving human subjects are not applicable to this PA.  Basic research

or clinical studies in which human tissues cannot be identified or

linked to individuals are excluded from the usual NIH policies on

gender and minority representation in human subjects.  However, every

effort should be made to include tissues from racial/ethnic minority

women when it is important to apply the results of the study broadly to

human populations, and this issue should be addressed by the

applicants.



APPLICATION PROCEDURES



Applications are to be submitted on form PHS 398 (rev. 9/91), available

at most institutional offices of sponsored research and may be obtained

from the Office of Grants Information, Division of Research Grants,

National Institutes of Health, Westwood Building, Room 449, Bethesda,

MD 20892, telephone, (301) 710-0267.  The format and instructions

applicable to regular research grant applications must be followed in

preparing a grant in response to this PA.



The number and title of the PA must be typed on line 2a of the face

page of the application and YES must be checked.  A signed, typewritten

original grant application, including the checklist, and five signed,

exact photocopies, must be mailed, in one package, to:



Division of Research Grants

National Institutes of Health

Westwood Building, Room 240

Bethesda, MD  20892**



REVIEW CONSIDERATIONS



Upon receipt, applications will be reviewed by the Division of Research

Grants for completeness.  Incomplete applications will be returned to

the applicant without further consideration.  Applications will be

assigned on the basis of established Public Health Service referral

guidelines.  Applications will be reviewed for scientific and technical

merit by study sections of the Division of Research Grants, NIH, in

accordance with the standard NIH peer review procedures.



Review Criteria



1.  The scientific and technical significance of the proposed research;

2.  The adequacy of the methodology to carry out the research;

3.  The qualifications and experience of the Principal Investigator and

staff;

4.  Reasonable availability of resources;

5.  Reasonableness of the proposed budget and duration;

6.  Other factors:  e.g., human subjects, animal welfare, and

biohazards



AWARD CRITERIA



Scientific merit and contribution to overall programmatic balance and

the availability of funds will be major criteria for making award

decisions.



INQUIRIES



Written and telephone inquiries concerning the scientific objectives

and scope of this PA are encouraged and may be directed to:



Richard A. Pelroy, Ph.D.

Division of Cancer Etiology

National Cancer Institute

Executive Plaza North, Room 530

6130 Executive Boulevard

Bethesda, MD  20892

Telephone:  (301) 496-9326

FAX:  (301) 496-1224



Direct inquiries regarding administrative and fiscal matters to:



Ms. Lauren Neumann

Grants Administration Branch

National Cancer Institute

Executive Plaza South, Room 242

6120 Executive Boulevard

Bethesda, MD  20892

Telephone:  (301) 496-7800, ext. 264

FAX:  (301) 496-8601



AUTHORITY AND REGULATIONS



This program is described in the Catalog of Federal Domestic Assistance

No. 93.393, Cancer Cause and Prevention Research.  Awards are made

under authorization of the Public Health Service Act, Title IV, Part A

(Public Law 78-410, as amended by Public Law 99-158, 42 USC 241 and

285) and administered under PHS grants policies and Federal Regulations

42 CFR 52 and 45 CFR Part 74.



.

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