Multidisciplinary Research On The Etiology And Prevention Of Breast Cancer

NIH GUIDE, Volume 22, Number 33, September 17, 1993

PA NUMBER:  PA-93-112



P.T. 34



Keywords:

  Cancer/Carcinogenesis 

  Disease Prevention+ 

  Etiology 



National Cancer Institute



PURPOSE



The Chemical and Physical Carcinogenesis Branch, Division of Cancer

Etiology (DCE), National Cancer Institute (NCI), invites

investigator-initiated grant applications for multidisciplinary

research on the etiology and prevention of breast cancer.



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 Program

Announcement (PA), Breast Cancer:  Etiology and Prevention, 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 202-783-3238.



ELIGIBILITY REQUIREMENTS



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

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

colleges, hospitals, laboratories, units of state or local

governments, and eligible agencies of the Federal government.

Applications from women and minority investigators are encouraged.

Foreign institutions are not eligible for First Independent Research

Support and Transition (FIRST) (R29) awards.



MECHANISM OF SUPPORT



Support of this program will be through the National Institutes of

Health (NIH) traditional research project grant (R01) or the FIRST

award (R29).  Applicants will be responsible for the planning,

direction, and execution of the proposed project.  Because the nature

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

the size of an award may vary also.  For FIRST awards, the total

direct costs of the five-year funding period may not exceed $350,000;

the direct costs in any one year may not exceed $100,000.  Except as

otherwise stated in this PA, awards will be administered under PHS

grants policy as stated in the Public Health Service Grants Policy

Statement, DHHS Publication No. (OASH) 90-50,000, revised October 1,

1990.



RESEARCH OBJECTIVES



Background



Breast cancer affects more women per year than any other cancer and

continues to be a leading cause of death in the United States.  It

has been estimated that about 18 percent of all female cancer deaths

in the U.S. will be due to breast malignancies and that approximately

46,000 women in the U.S. will die of breast cancer in 1993.  The

average mortality rate for breast cancer in the U.S. is 27.5 per one

hundred thousand.  Further, recent data point to an unexplained

increase in breast cancer incidence and mortality rates.  Since

breast cancer incidence increases with age, this finding is of

particular concern because the "baby boom" generation is entering

middle age and medical advances continue to increase average U.S.

life expectancy.  The NCI has made breast cancer one of its highest

priorities and it is expected to be a continuing priority of the NCI

and the U.S. Congress for the foreseeable future.



The following research questions are relevant to this initiative:

(1) What is the target cell in the breast that ultimately becomes the

cancer cell and what are the characteristics that could make it

identifiable?  (2) What molecular events initiate breast cancer and

what factors (diet, hormones, etc.) stimulate proliferation of the

initiated cell?  (3) What is the natural history of breast cancer and

what new markers, among the probes now available or under

investigation, might be most promising for characterizing normal

breast tissue at its various stages of development, distinguishing

normal from abnormal, following the natural history longitudinally,

and assessing the efficacy of chemopreventive agents?  (4) What is

the mechanism that conveys a protective effect of first birth on

breast cancer risk in humans?  (5) What are the critical hormonal

interactions with genetic constituents that can lead to breast cancer

and how can chemopreventive agents modulate the outcome?



Research Goals and Scope



The objectives of this PA are designed to encourage

investigator-initiated multidisciplinary research to address research

questions in the etiology and prevention of breast cancer.  A

discussion of specific topic areas that are encouraged by this PA

follows.



Endocrinology (Hormones/Growth Factors) - The role of hormones in

etiology and chemoprevention that may affect neoplastic processes,

either by acting alone or in conjunction with non-hormonal chemical

carcinogens and inhibitors, should be studied in vitro and in vivo.

Endocrine imbalance, namely in estrogens and progesterone, is

considered highly pertinent in the etiology of breast cancer.  The

most characteristic property of these hormones is their elicitation

of cell proliferation and differentiation in breast tissue.  In

addition, hormonal interactions with genetic constituents and their

receptors, and the modulating effects of chemopreventive agents,

should be investigated.  Recently, estrogen/progesterone-driven cell

proliferation has been proposed as the critical element leading to

breast cancer in women.  Also of interest is the role in mammary

anticarcinogenesis of members of the steroid-thyroid hormone

superfamily of nuclear receptors and their ligands (such as

retinoids, retinoic acid receptors, and retinoid X receptors).

Further, studies on the efficacy and mechanisms of combination

chemoprevention of breast cancer, including the use of cytokines, are

encouraged.



Anticarcinogenesis/Chemoprevention - Chemoprevention studies are

encouraged on the inhibition/suppression of breast cancer in vivo and

in vitro, including the use of appropriate sources of human

tissue/cell lines.  Also of interest are markers of intermediate

endpoints as they relate to determining the efficacy of

chemopreventive agents.  These endpoints may include hormone

determinations (estrogen, progesterone, prolactin and other peptides,

growth factors and their receptors, estrone metabolites), oncogenes

and tumor suppressor genes and their products, and susceptibility

genes.  A growing number of promising chemopreventive agents for

mammary carcinogenesis have been identified in experimental animal

model systems, for which the mechanisms of action require detailed

investigations (e.g., N-acetylcysteine, anethole trithione,

carbenoxolone, curcumin, fumaric acid, glycyrrhetinic acid,

oltipraz).  Further, studies are needed on the mechanisms of action

of chemoprotective/chemopreventive agents that emphasize the effects

on phase I and phase II enzyme systems in breast cancer prevention

and that are directed at elucidation of the proximate and ultimate

chemical structures responsible for chemoprotection/chemoprevention.

Investigations on the role of free radical inhibition in the

prevention of breast cancer are also needed.  Discovery and chemical

identification of naturally-occurring inhibitors of mammary

carcinogenesis, as well as chemical synthesis and modulation of the

structure of compounds, are needed in order to understand

structure-activity relationships as a basis for chemoprevention of

breast cancer.



Molecular Genetics - There is evidence in animal model and human

studies that mutations and chromosomal changes are involved in the

neoplastic process in breast cancer.  It is also evident from studies

in colon cancer and other models that multiple changes ("hits") are

necessary for the initiation and progression of normal breast cells

to evolve to the final neoplastic and metastatic state.  Additional

studies are needed to define the molecular events involved in the

etiology of breast cancer, to identify molecular markers for each

stage in the initiation and progression of the disease, and to

identify specific genes and gene products involved in the process.

For these studies on the genetics of breast cancer, additional

relevant animal and cell culture models may be needed.  Transgenic

technologies may be especially powerful.



Cell Biology - Studies of the organization, proliferation and

differentiation of breast tissue, principally primary human luminal

mammary epithelial (HLME) cells, during normal development and

progression to malignancy are needed, including studies of the

interaction between normal and malignant epithelial cells and the

surrounding stroma.  Research on the regulation of cell proliferation

of normal or tumor cells is needed, both in primary culture and in

primary transplants in immunodeficient animal hosts.  The

differentiating effects of hormones and growth factors on normal

mammary epithelial cells from premenopausal women at various

physiological states needs to be studied.  Guanine nucleotide binding

proteins (G proteins), which are associated with mammary cell growth

and differentiation, need to be understood for their role in

endocrine tumors of the breast.



Studies are needed to obtain efficient transformation of breast

tissue, particularly primary HLME cells, to pre-malignant and

malignant cells in vitro and in vivo, emphasizing current concepts of

molecular and hormonal carcinogenesis.  The specific objectives of

such studies are to (1) define conditions, both in primary cultures

and in immunodeficient animals with xenografts, that allow

transformation of primary HLME cells using chemical and/or physical

agents as well as hormones and growth factors, and (2) delineate

markers (e.g., biochemical, cytological, histopathological,

molecular) that identify specific stages of in vitro and in vivo

mammary epithelial transformation and distinguish particular

preneoplastic states in the multi-step process.



The hormone-mediated growth advantage of early preneoplastic breast

lesions, compared to normal breast epithelial tissue at different

stages of differentiation, needs to be characterized and the

consequences elucidated.  Since the development of these

preneoplastic breast lesions is likely to be hormonally driven, early

estrogen response genes, as well as growth factors and

protooncogenes, should be examined.  Following hormonal exposure,

primary animal and human breast cells in culture should be studied

and correlated with in vivo data.  Aberrant gene expression should be

studied initially at the chromosomal level and then at the level of

the gene.  Gene amplification and suppression, as well as chromosomal

abnormalities due to hormonal exposure, should provide important

clues to progressive breast cell alterations leading to neoplastic

development.



Metabolism - Many polycyclic aromatic hydrocarbons (PAHs) have been

established in animals as breast carcinogens.  Metabolic activation

of PAHs in various tissues is known to proceed by two major

mechanisms, one- and two- electron oxidation.  The interaction of

reactive metabolites with potential target molecules (DNA, RNA,

protein) and the relative contribution of the two oxidation pathways

in mammary tissue is unknown.  Studies also need to be undertaken on

which breast tissue P450 isozymes are involved in metabolic

activation/detoxification and on the nature of enzyme induction

itself.  Breast tissue from at-risk populations and animal models can

be used for the detection and quantitation of DNA adducts of these

mammary carcinogens in target tissue.  Since many of these adducts

are not widely available as reference standards, synthesis of adducts

is also an area of emphasis that needs to be coordinated with efforts

to identify and study markers of exposure and to determine carcinogen

dosimetry.



The metabolism of xenobiotics in breast tissue may lead to the

generation of free radical or oxygen radical intermediates.  The

reaction of these radicals with lipids can lead to lipid

peroxidation, with subsequent cellular and molecular changes.

Additional studies on the role of different types of dietary fat in

the process of lipid peroxidation, and its effects on the

carcinogenic process in breast tissue, are needed.



Several demonstrated rodent mammary carcinogens are present in

tobacco smoke including heterocyclic amines (PHIP), nitropyrenes (1-

and 4-), dinitropyrenes (1,3- and 1,8-), and PAHs [benzo(a)pyrene,

benzo(c)phenanthrene, dibenzo(a,l)pyrene].  The metabolism of these

compounds needs to be examined in human breast tissue/cell lines and

compared with other organs; standards for these compounds and most of

their metabolites are available in the NCI Chemical Carcinogen

Reference Standards Repository.



Epidemiologic Correlates/Interspecies Comparisons -  Epidemiologic

investigations have revealed that women who have a full-term

pregnancy early in their childbearing years have a reduced risk of

breast cancer.  The biologic basis for this protection is not

understood yet the observation suggests that prevention opportunities

exist.  Basic research is needed on the protective effect of early

full-term pregnancy on the incidence of breast cancer, specifically

the effects of the length of the period between menarche and first

full-term pregnancy which might be critical for the initiation of

breast carcinogenesis.  The hormonal levels and bioavailability of

estrogen and other mammogenic hormones in premenopausal women (parous

compared to nulliparous) should be studied.  Animal models of this

protective effect could be of significant value.



Retroviruses - The demonstrated etiologic role of retroviruses in

mouse mammary carcinoma and the possible analogy to human mammary

carcinoma make it important to determine if retroviruses play a role

in the etiology of human breast cancer.  New findings report the

identification of several messenger RNA (mRNA) species, including a

full length mRNA of the human endogenous retrovirus (HERV) sequence

and its probable association with retroviral particles observed in a

human teratocarcinoma cell line.  These observations and the new

technology used provide a basis for additional studies to examine

this and other endogenous retroviruses for possible etiologic

significance in human breast cancer.  Accordingly, applications are

encouraged to address the possible role of endogenous and also

exogenous retroviruses in the etiology of human breast cancer.



STUDY POPULATIONS



SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH

POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL

RESEARCH STUDY POPULATIONS



The NIH has formulated policies concerning inclusion of women and

minorities in clinical research study populations. It is policy that

applicants for NIH clinical research grants and cooperative

agreements are required to include minorities and women in study

populations so that research findings can be of benefit to all

persons at risk of the disease, disorder or condition under study;

special emphasis must be placed on the need for inclusion of

minorities and women in studies of diseases, disorders and conditions

which disproportionately affect them.  This policy is intended to

apply to males and females of all ages.  If women or minorities are

excluded or inadequately represented in clinical research,

particularly in proposed population-based studies, a clear and

compelling rationale must be provided.



For the purpose of this policy, clinical research is defined as human

biomedical and behavioral studies of etiology, epidemiology,

prevention (and preventive strategies), diagnosis, or treatment of

diseases, disorders or conditions, including but not limited to

clinical trials.  This PA does not seek applications for clinical

research.



Basic research in which human tissues cannot be identified or linked

to individuals are excluded from the policy on women and minorities.

However, every effort should be made to include human tissues from

women and racial/ethnic minorities when it is important to apply the

results of the study broadly, and this should be addressed by

applicants.



APPLICATION PROCEDURES



Applications are to be submitted on the research grant application

form PHS 398 (rev. 9/91) and will be accepted on the standard receipt

dates as indicated in the application package.  The application

package is available at most institutional offices of sponsored

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

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

Bethesda, MD 20892, telephone 301-435-0714; and from the NCI Program

Director named below.



Applications for the FIRST Award (R29) must include at least three

sealed letters of reference attached to the face page of the original

application.  FIRST Award (R29) applications submitted without the

required number of reference letters will be considered incomplete

and will be returned without review.



The title and number of the PA must be typed in Section 2a on the

face page of the application.  The signed, typewritten original of

the application and five signed, exact, clear, and single-sided

photocopies, must be sent or delivered in one package to:



Division of Research Grants

National Institutes of Health

Westwood Building, Room 240

Bethesda, MD  20892**



REVIEW CONSIDERATIONS



Applications will be assigned on the basis of established PHS

referral guidelines.  Upon receipt, applications will be reviewed for

completeness by NCI program staff.  Incomplete applications will be

returned to the applicant without further consideration.

Applications will be reviewed for scientific and technical merit by

study sections of the DRG, NIH, in accordance with standard NIH peer

review procedures.  A second level of review will be by an

appropriate national advisory council or board.



AWARD CRITERIA



Applications will compete for available funds with all other approved

applications.  Awards will be made primarily on the basis of

scientific merit but responsiveness to the PA, overall program

balance, and the availability of resources are important

considerations that will be taken into account.



INQUIRIES



Written and telephone inquiries concerning the objectives and scope

of this PA, or inquiries about whether or not specific proposed

research would be responsive, are encouraged and may be directed to:



Dr. David G. Longfellow

Division of Cancer Etiology

National Cancer Institute

Executive Plaza North, Suite 700

Bethesda, MD  20892

Telephone:  (301) 496-5471

FAX:  (301) 496-1040



Written and telephone inquiries of a budgetary, administrative,

and/or policy nature may be directed to:



Ms. Joseph H. FitzGerald

Grants Administration Branch

National Cancer Institute

Executive Plaza South, Suite 243

Bethesda, MD  20892

Telephone:  (301) 496-7800, Ext. 15

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 the 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 or 45 CFR Part 92.

This program is not subject to the intergovernmental review

requirements of Executive Order 12372 or Health Systems Agency

review.



It should be noted that the National Institute of Diabetes and

Digestive and Kidney Diseases (NIDDK) has an interest in basic

research to elucidate the nature, function, and action of hormones,

growth factors, and their receptors in general, but not in the

specific emphasis of this PA, which is the role of hormones as

co-factors or initiators/promoters of carcinogenesis in the breast.

Applications that do not address this specific theme will be given an

institute assignment based on the "Referral Guidelines for Funding

Components of PHS 1992."



.


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