A PRACTICAL HANDBOOK OF DUTIES AND RESPONSIBILITIES
FOR THE OFFICERS OF THE CARCINOGENESIS SPECIALTY SECTION
Upon being elected as an officer of the Carcinogenesis Specialty Section (CSS) the first question one asks is “So, what am I supposed to do?. Details of the rules and regulations pertaining the CSS can be found in the by-laws on file with the Society of
Toxicology (SOT). This handbook, however, is a practical guide put together by a number of past and current officers. It contains duties, timetables, examples, and helpful hints. Please add to it and pass it on to the succeeding officers. This handbook is dedicated to those people willing to devote their time to the success of this dynamic
Specialty Section. Updated March 13, 2002 by Byron Butterworth
Past President
Elections
Lead the nominating committee for new officers. Work with the current presidency and councilors for suggestions. The one-year term officer elected every time is the Vice President Elect. Two-year term officers include the Secretary/Treasurer and the councilors. The ballots should go out in early January. So, the legwork should be done in December. Candidates must be members of the CSS. After agreeing on the best list, the Past President will contact each potential candidate to see if they will agree to run.
The Past President will then coordinate with the President and
Secretary/Treasures to convey the final list of candidates to the SOT Headquarters. For example, the contact person in 2002 at SOT was Ms. Rita Rose. SOT then sends out the ballots via e-mail. Members vote via return e-mail. SOT then informs the President of the results, who informs the winners and thanks all who ran.
Annual Council Meeting
Attend the annual CSS council meeting at the SOT Annual Meeting.
President
Elections
Work with the Past President to put together a slate of candidates and hold the election in January (see Past President).
Newsletter
Work with the Secretary/Treasurer to issue at least two issues of the CSS newsletter. A Pr esident’s message is always included (see Appendix for an example of a newsletter). It is always a good idea to have the Secretary/Treasurer review the
Presidents message. The newsletter should inform the Section members about activities and contain reminders about deadlines such as submission of student awards
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and requests for suggestions for symposia. Solicit short informative articles from the membership on their research and emerging issues.
Preparations for the Annual Meeting
As the annual meeting approaches, SOT Headquarters will contact the President regarding CSS meetings to be held. There are generally two. The first is the CSS
Reception. SOT will help set dates and times. A form needs to be filled out requesting room size, microphone on podium, and choice of food. The second meeting is the CSS council meeting. It often makes sense to schedule that meeting in the same room as the reception, but a couple of hours earlier. A form also needs to be filled out for any tables, food, or AV equipment for that meeting.
Annual Council Meeting
Preside at the annual CSS council meeting at the SOT Annual Meeting. Present the results of the elections and student awards. Discuss any Specialty Section
Business.
Annual Report
SOT Headquarters asks for an Annual Report in May from the Specialty Section.
The request goes to the President, but is really something that is best done with the
Secretary/Treasurer. Working together means that items are not likely to be left out. An example of an Annual Report is in the Appendix.
Budget
SOT Headquarters sends the President a CSS Budget summary. It contains Net
Assets allocated by SOT and expenses toward those assets. Since SOT is in control of most items, there is little to do but watch the bottom line. The Secretary/Treasurer should be kept in the loop. Expenses are generally for plaques and checks for the
Student Awards and for food for the Reception. Symposia speakers who are SOT members pay their own way. Guest speakers sponsored by the CSS have their travel paid. So, that is one expense to watch. However, lately the SOT has taken over the guest travel in their budget, rather than charge it to the individual specialty sections.
Keep up to date on the current policy.
CSS Sponsored Symposia, Workshops, and Continuing Education Courses
At the annual meeting the CSS sponsors symposia, workshops, and continuing education courses. The Vice President and President are responsible for soliciting suggestions from the CSS membership and submitting them to the SOT Program
Committee (see Vice President).
The President of the CSS writes a letter of sponsorship that is sent to the SOT
Headquarters to support each proposed program. Any specific symposium may have the sponsorship of more than one Specialty Section. The President will spend some time on the phone and via e-mail with presidents of the other Specialty Sections asking for, and being asked for sponsorship. The President then writes the appropriate letters of sponsorship to the SOT Headquarters. This can be done via attachments to e-mail.
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Workshops and Special Meetings
The CSS may during the course of the year sponsor a special workshop or scientific meeting. This requires a great deal of extra effort on the part of the organizer.
People have been so overwhelmed with work that no volunteers have come forward for the past few years. Sponsoring such a meeting is laudable, if one can find those willing to put in the effort. This activity is optional and is generally proportional to the enthusiasm of the current officers.
CSS Reception
The CSS Reception is held in conjunction with the SOT Annual Meeting. The
President presides at this meeting. The order of business is generally as follows:
Welcome Message - President
Announcement of Election Results - President
Presentation of Student Awards - Vice President
Solicitation for Symposia and Continuing Education Courses - Vice-President Elect
Introduction of incoming President (current VP) - President
Wrap-up and thank you to outgoing President and officers including presentation of a plaque to the outgoing President - Vice President
Vice President
CSS Sponsored Symposia, Workshops, and Continuing Education Courses
At the annual meeting the CSS sponsors symposia, workshops, and continuing education courses. The Vice President and President are responsible for soliciting suggestions from the CSS membership and submitting them to the SOT Program
Committee. Members of the CSS are involved in cutting-edge research and we want to share that excitement with our fellow SOT members. Organizing a symposium that includes one’s research is informative for the SOT membership and prestigious for the research scientist.
Because everyone is so overcommitted, it often requires encouragement to get an individual to put together and chair a symposium or continuing education course.
The Vice President and President should identify important advances in the field and contact those individuals who may be willing to put a program together. the President and Vice President should provide guidance to those who are willing to organize a symposium or course. Look at the current Program Book for guidance as to types of programs, number of speakers, organization, etc. Usually an introduction with 4 speakers is about right for a symposium. Be sure to be a resource and work closely with the organizers, so that they don’t go astray in formulating their programs. Often you will be pleasantly surprised and someone will come forward with a great suggestion with speakers already contacted.
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The person putting together the program usually serves as the chairperson.
Symposia organizers and chairpersons MUST be SOT members - no exceptions. He or she comes up with a list of speakers and topics and makes sure that those individuals are willing to make the commitment to speak. Those speakers should be told up front by the organizing person that this is a proposed program . The programs are submitted in April to the SOT Program committee on the official form.
NOTE - If the Program Committee does not approve of the symposium, it dies.
This can be a serious problem that results in frustration and hurt feelings. Individuals can put in a lot of work that comes to nothing. Then they have to call each speaker and tell them the bad news. SOT should re-think the process, but for now, it is how things are done. Be prepared to be sympathetic and to use your anger management skills.
For example, in 2001 we had several excellent symposia that were not accepted by the program committee. It was a less than pleasant situation.
Note that the submissions for symposia are due in April. That means that the incoming Vice President and President have to get to work to line up organizers, chairpersons, and symposia months before that. If you wait till the March SOT Annual
Meeting, you will have your backs to the wall.
Student Awards
The Vice President is responsible for the student awards. Students represent the future of the CSS. The Student Awards provide encouragement and incentive for their participation. The students are recognized at the CSS reception at the annual meeting.
The winners receive recognition plaques and monetary awards for 1st ($500), 2nd
($300), and 3rd ($100) place. Application involves submission of the meeting abstract and a letter of sponsorship from the graduate student advisor. Abstracts should be submitted by December 1 to the current Vice President. The announcement of the student award competition should be made early in the fall by both SOT Headquarters
(see announcement in the Appendix) as well as in the newsletter.
The applications are judged by a committee made up of the Vice President and the CSS Councilors. After the judging, each winner is informed by the Vice President.
Informing the winners is important, to make sure that they are present at the CSS reception. The Vice President fills out the RECOGNITION ORDER FORM that goes to the SOT Headquarters. For example, in 2002 that contact was Ms. Rita Rose. That form lists the winners and is the means of ordering 1) The certificates; 2) The plaques; and 3) The award checks. The Vice President picks up all this material from the SOT
Headquarters at the annual meeting. The certificates should be given right away so that they can be displayed on the poster. You may also want to attach a blue, red, or white ribbon, if you wish. If a winning student is giving a talk, the fact that they are a winner should be announced by the Chairperson of the session. The plaques and checks are awarded by the Vice President at the CSS reception. See the Appendix for an example of the letter to an award winner.
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Plaque for the Outgoing President
Beginning in 2001 we felt that it was appropriate and thoughtful that the outgoing
President receive a plaque from the Specialty Section expressing appreciation for his or her service. The Vice president should have a plaque made up and charge the cost to the Specialty Section. A modest plaque of about 8 x 10 inches or so is all that is needed. The plaque is awarded by the Vice President at the CSS Reception.
Annual Council Meeting
Attend the annual CSS council meeting at the SOT Annual Meeting.
Vice President Elect
CSS Sponsored Symposia, Workshops, and Continuing Education Courses
At the annual meeting the CSS sponsors symposia, workshops, and continuing education courses. The Vice President and President are responsible for soliciting suggestions from the CSS membership and submitting them to the SOT Program
Committee (see Vice President).
Note that the submissions for symposia are due in April. That means that the
Vice President and President have to get to work to line up organizers, chairpersons, and symposia months before that. If you wait till the March SOT Annual Meeting, you will have your backs to the wall. So, as Vice President Elect, you will become Vice
President at the Annual Meeting in March. You need to begin working before that with the President-to-be to line up symposia and continuing education courses.
Annual Council Meeting
Attend the annual CSS council meeting at the SOT Annual Meeting.
Secretary/Treasurer
Elections
Work with the Past President to put together a slate of candidates and hold the election in January (see Past President).
Budget
SOT Headquarters sends the President a CSS Budget summary. It contains Net
Assets allocated by SOT and expenses toward those assets. Since SOT is in control of most items, there is little to do but watch the bottom line. The Secretary/Treasurer should be kept in the loop. Expenses are generally for plaques and checks for the
Student Awards and for food for the Reception. Symposia speakers who are SOT members pay their own way. Guest speakers sponsored by the CSS have their travel paid. So, that is one expense to watch. However, lately the SOT has taken over the guest travel in their budget, rather than charge it to the individual specialty sections.
Keep up to date on the current policy.
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Newsletter
Work with the President to produce at least two issues of the CSS newsletter
(see President and example in the Appendix).
Annual Council Meeting
Attend the annual CSS council meeting at the SOT Annual Meeting.
Councilor
Elections
Serve as a resource for the Past President to help put together a slate of candidates for the election in January (see Past President).
Student Awards
Serve on the student awards judging committee headed by the Vice President
(see Vice President). Visit each winning student presentation, introduce yourself as a
Council Member and let them know we appreciate their participation.
CSS Sponsored Symposia, Workshops, and Continuing Education Courses
At the annual meeting the CSS sponsors symposia, workshops, and continuing education courses. Encourage the membership to take the responsibility for such a program (see Vice President).
Newsletter
Encourage the membership to submit articles for the Newsletter (see
Secretary/Treasurer)
Annual Council Meeting
Attend the annual CSS council meeting at the SOT Annual Meeting.
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APPENDIX
Example Announcement for the Student Awards to be sent out by SOT Headquarters
2002 Student Awards Information for the Carcinogenesis Specialty Section of the
Society of Toxicology
Specialty Section: Carcinogenesis
Award Requirement: Submit abstract and letter of sponsorship from graduate student advisor.
Areas of Research: Carcinogenesis
Deadline: December 1, 2001
Contact: ( Obviously, use current Vice President ) Dr. Samuel Cohen, University of
Nebraska Medical Center, Pathology/Microbiology, 983135 Nebraska Medical Center,
Omaha, NE 68198-3135, phone: (402) 559-6388, e-mail: scohen@unmc.edu
Winner Receives: Recognition plaques and monetary awards to 1st ($500), 2nd ($300), and 3rd ($100) place winners
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Example of the letter informing the student award winners
Dear Ms. Auyeung:
On behalf of President Byron E. Butterworth, the judging committee and myself, it is my pleasure to inform you that you have won first place in the Student Awards
Competition of the Carcinogenesis Specialty Section of the Society of Toxicology for
2002. Your abstra ct, “The AH Receptor and AH Receptor Nuclear Translocator
Mediates Stimulation by Oltipraz of the Xenobiotic Response Element in the Rat
UGT1A6 Gene,” was excellent and clearly describes research of the highest quality.
Your mentor, Dr. Joe Ritter, was very supportive and I am sure is pleased and proud of your accomplishment.
The first place award consists of a check for $500, a plaque, and a ribbon for your poster. These will be presented to you at our reception for the Carcinogenesis
Specialty Section at the annual meeting of the Society of Toxicology in Nashville, March
20, 2002.
Please let me know if you have any questions. Again, congratulations on a job well done.
Sincerely yours, copy: Dr. Joe Ritter
Dr. Byron Butterworth
Samuel M. Cohen, M.D., Ph.D.
Vice President and “Chair of the Judging Committee
Carcinogenesis Specialty Section
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Example of and Annual Report
Carcinogenesis Specialty Section Annual Report : 2000-2001
I. Introduction
President
Vice President
Vice President Elect
Secretary/Treasurer
2000-2001
Yvonne Dragan
Byron Butterworth
Sam Cohen
Jennifer Counts
2001-2002
Byron Butterworth
Sam Cohen
Jon Cook
Jennifer Counts
Councilors
Past President
David Warshawsky
Jane Allen
James Yager
2000-2001 Annual Meeting Date: March 26, 2001
Jane Allen
Howard Glauert
Karen Steinmetz
Yvonne Dragan
II. Activities
The Carcinogenesis Specialty Section Annual Meeting was held on March 26,
2001 in San Francisco in association with the Society of Toxicology Annual Meeting.
Approximately 30 people were in attendance. President Yvonne Dragan led the meeting. She reviewed the goals of the Specialty Section, introduced the winners of the election, and noted business items of importance. Sam Cohen reminded those interested in proposing a Symposium or Continuing Education course for 2002 to get that information to him by the April deadline. Byron Butterworth presented the Student
Presentation Awards, discussed future goals, and recognized Yvonne Dragan for her dedicated service.
Student Award Winners Were
First Place: Jennifer L. Ariazi
Immature Rat Mammary Epithelial Cells (RMECs) are More Susceptible than Mature
RMECs to the Cytolethal, Carcinogenic, and Mutagenic Effects of N-Nitroso-N-
Methylurea
McArdle Laboratory for Cancer Research
University of Wisconsin, Madison
Second Place: Tasha R. Smith
Amino Acid Substitution Variants of APE1 and XRCC1 Genes Associated with Ionizing
Radiation Sensitivity
Department of Cancer Biology
Wake Forest School of Medicine
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Third Place: Angela Siesky
Modulation of Hepatic Cell proliferation and Oxidative Stress in 2-Butoxyethanol Treated
Mice
Department of Pharmacology and Toxicology
Indiana University School of Medicine
III. Financial Report
Balance as of 7/1/2000
Revenue from Dues
Non-dues Revenue
Expenses
Balance as of 6/30/01
IV. Future Plans
2002 Symposia and Continuing Education Courses Proposed by Members of and
Sponsored by the Carcinogenesis Specialty Section are as follows:
Symposia
Scientific Basis for Reducing Harm from Cigarette Smoking
The Status of Toxicogenomics in Toxicology
Rodent Models of Endocrine Neoplasia: Are they Relevant to Human Risk Assessment
Carcinogens Exhibit Thresholds: The Value of Mechanistic Studies
Continuing Education Course
Internal Dosimetry: Measurement of DNA Damage as and Indicator of Internal Exposure to Genotoxicants
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Sample Newsletter
Dear Specialty Section Members:
I am writing this message saddened by the recent loss of life of so many innocent victims at the hands of terrorists. I know that we all send our deepest sympathies to those who have lost family or friends in those senseless acts. Compassion, knowledge and wisdom have formidable enemies in hatred, ignorance, and superstition. Acts of destruction are easy, the processes of learning and creation are difficult. I reflect on the numbers of people who have dedicated their careers to understanding, preventing, and curing cancer and ministering to those afflicted. Progress has come as a result of an ever-growing knowledge base passed from generation to generation. We are fortunate to be able to contribute at a time when information and the tools for learning are so great. We are privileged, and somewhat sheltered, to be able to work within a worldwide community of scientists where compassion, knowledge and wisdom are, indeed, paramount. However you are choosing to cope with the sorrow, may your efforts help in achieving the peace longed for by so many.
Don’t forget that the deadline for the electronic submission of abstracts for the
Annual Meeting of the Society of Toxicology is October 1, 2001. Members of the
Carcinogenesis Specialty Section (CSS) have always provided a major contribution to the Meeting and I am sure that this tradition will continue. One of the most important activities of our members is the training of students. These individuals represent the future of our discipline and we need to encourage their participation. The Student
Awards of the CSS provide a great way of doing this. The students are recognized at the CSS Reception at the annual meeting. The winners receive recognition plaques and monetary awards for 1st ($500), 2nd ($300), and 3rd ($100) place. Application is simple and requires only submission of the meeting abstract and a letter of sponsorship from the graduate student advisor. For the Student Awards: abstracts should be submitted by December 1, 2001 to Dr. Samuel Cohen, University of Nebraska Medical
Center, Pathology/Microbiology, 983135 Nebraska Medical Center, Omaha, NE 68198-
3135.
As Vice President, Dr. Cohen is responsible for the judging this year. Our students are dedicated and energetic. Participation in the awards competition provides recognition and a spirit of community.
Remember also that it is not too early to begin to think of topics for symposia and continuing education for the next annual meeting. Myself or any of the other CSS
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officers will be glad to discuss your ideas or any suggestions you might have to improve our organization. The CSS officers this year are: President - Byron Butterworth, Vice
President - Sam Cohen, Vice President-Elect - Jon Cook, Secretary/Treasurer - Jennifer
Counts, Councilors - Jane Allen, Howard Glauert, and Karen Steinmetz, Past-President
- Yvonne Dragan. The success of the Society and the CSS is, of course, only a reflection of your efforts. Thank you for your involvement and support.
Sincerely,
Byron E. Butterworth
President
Please send Jennifer Counts articles and information for inclusion in the CSS newsletters (counts.jl@pg.com or by phone 513-626-0023). Your continued support will ensure that this remains an excellent specialty section.
Michelle Bennett
Livermore National Labs
Of the approximately 180,000 cases of breast cancer that are diagnosed among women this year, 7% can be attributed to the genetic inheritance of mutations in breast cancer susceptibility genes. Seventy percent of breast cancer is believed to arise as the result of a combination of genetic factors and environmental exposures. Epidemiologic studies provide evidence that environmental factors, alone or in combination with genetic factors influence breast cancer development in women. Hormone replacement therapy (HRT) is associated with an increased risk for breast cancer in postmenopausal women (1,2). HRT increases mammographic breast density, a risk factor for breast cancer, by inducing ductal growth and proliferation (3). High birth weight, likely influenced by hormonal exposures in utero, was identified as a risk factor for breast cancer development (4). Observations like these have focused attention on the timing of exposure as a critical risk factor for breast cancer development. In addition, the effects of endogenous or exogenous factors, such as oral contraceptives, pregnancy and smoking, are being studied in high-risk populations such as BRCA1 and BRCA2
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mutation carriers. Such studies provide information about gene-environment interactions which may be useful for making science-based recommendations about lifestyle choices that influence breast cancer risk (5-7).
Whereas epidemiologic studies are necessary and of immense value, model systems can be used to elucidate health outcomes from exposures and to define their mechanisms of action. Animal models provide a means for examining the effect of environment on breast cancer development alone or in combination with variables such as genetic alterations and timing or frequency of exposure. The genetic alterations that are most commonly studied rodent models include the gain of function mutations
(oncogene activation) that can be studied in transgenic animals, and the loss of function mutations (tumor-suppressor gene inactivation) which are typically evaluated in mice with genes altered by gene-targeting and homologous recombination or mutagenesis techniques. Carcinogen treated rat models have been used extensively to define the consequences of single chemical exposures during different periods of mammary gland growth and development. The use of rodent systems permits an exposure to be specifically tested in the context of all organ systems, a critical consideration given one chemical can have dramatically different organ-specific effects. In addition, these models enable investigations into exposure effects, elucidate the mechanisms which alter risk to breast cancer, make predictions about human relevance, and provide preliminary data and rationale for the testing of putative therapeutics or preventative treatments for breast cancer.
Mammary Gland Development
Susceptibility to environmental exposures may be more complex in the mammary gland because its development occurs in multiple stages. Fetal development of the mammary gland rudiment is governed by tissue interactions in both males and females.
In females, the onset of ovarian function during puberty drives morphogenesis such that the mammary ducts elongate and branch into the surrounding stroma. This burst of proliferation ceases when the mammary ducts reach the limits of the fat pad. Massive differentiation of the mammary gland, triggered by pregnancy, results in lobulo-alveolar development, culminating in milk-producing structures at parturition. After weaning involution takes place and is characterized by massive apoptosis. The evaluation of the mammary gland in a whole animal systems presents a powerful opportunity to evaluate the consequences of genetic and environmental factors on normal mammary gland growth and differentiation, non-neoplastic changes, and progression to neoplasia as they relate to the timing of exposure and the development of the mammary gland.
Rodent Models for the Study of Breast Cancer
The carcinogenic process from an initiating event to tumor promotion and development is widely accepted to result from the accumulation of mutational events.
The identification of the genes in which these mutations arise during promotion and progression largely include proto-oncogene and tumor suppressor genes. Numerous transgenic and gene-deficient mice have been developed to model different aspects of
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breast cancer. Rats and mice are also used to understand better the consequences of exposure to agents suspected of causing and/or preventing mammary tumor induction by chemical treatment. The following sections will describe three commonly used systems in which to model human breast neoplasia. The following paragraphs represent a small sampling of the many models currently available.
Transgenic Mouse Models
There are two complementary transgenic mouse models in which to study the consequences of Her-2/Neu oncogene activation. The models are relevant to human cancer because patients whose breast tumors overexpress Her-2/Neu have reduced survival and an increased risk of metastasis compared to patients whose tumors do not.
Approximately 30% of breast tumors overexpress the Her-2/Neu oncogene.
The mouse models that include the MMTVneu transgenic mouse, which harbors a mutated form of the neu gene under the control of the mouse mammary tumor virus
(MMTV) promoter (8), and MMTV/wild-type n eu mice, that harbor the neu protooncogene under the control of the MMTV promoter (9). The MMTVneu transgenic mice develop mammary tumors with an incidence of 70% by 21 weeks of age, which varies depending on diet (10). At eight weeks of age these mice have multiple hyperplastic and dysplasic nodules in their mammary glands which progress to form mammary adenocarcinomas, and are histologically similar to human comedocarcinomas (reviewed in (11)). The strong evidence supporting the view that the overexpression of cneu played a role in breast cancer development led to the creation of MMTV/wild-type n eu mice. This mouse model develops focal mammary adenocarcinomas surrounded by hyperplastic mammary epithelium by seven months of age with frequent metastasis to the lung (9). Molecular analysis of the tumors revealed that the neu transgene had been mutated resulting in constitutive expression (reviewed in (12)).
The dysregulation of cyclins, proteins that activate cyclin-dependent kinases to regulate progression through the cell cycle, has been associated with breast cancer development in women. In particular, cyclins D1 and E have been reported to be overexpressed in human breast cancer cell lines and tumor samples (13-15).
Transgenic mice have been generated to model overexpression of both cyclin D1 and
E . MMTV/ cyclin D1 mice are characterized by the development of lobulo-alveolar structures in the mammary gland after sexual maturity and mammary adenocarcinomas by 18 months of age (16). Transgenic mice overexpressing cyclin E under the control of
-lactoglobulin (BLG) promoter have also been characterized (17). In general,
BLG/ cyclin E mice develop transient hyperplastic mammary glands while they are lactating and develop mammary tumors with about 12% incidence.
Scatter factor (SF), also known as hepatocyte growth factor (HGF) and designated HGF/SF, plays a role in mammary gland ductal morphogenesis by inducing branching of the ducts (18). HGF/SF is produced in the stromal tissue surrounding the mammary ducts and binds to the c-Met receptor expressed by the epithelial cells.
HGF/SF and c-Met accumulate in breast tumors and is associated with metastatic
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characteristics (19-21). Two transgenic mouse strains have been described that express an activated form of the Met oncogene under the control of the metallothionein promoter (22,23). In one instance, the mice develop hyperplastic nodules that progress to mammary tumors by 14 months of age, in addition to tumors at other sites (22), while in the other model, the mice develop metastatic mammary tumors (23).
Targeted Mutations in Breast Cancer Susceptibility Genes
Gene targeted mice have been have been generated for all major breast cancer susceptibility genes including BRCA1 , BRCA2 , p53 , PTEN , ATM , and APC . The study of gene-deficient mice with different genetic backgrounds, alone or in combination with other breast cancer susceptibility, modifier genes, or exposures may provide information about the variables that influence or protect against breast cancer development.
Women who inherit mutation in the BRCA1 and BRCA2 breast cancer susceptibly genes have up to an 85% chance of developing breast cancer in their lifetimes. Numerous investigators have developed mice with targeted mutation in these genes. The inheritance of a single mutated copy of Brca1 or Brca2 does not increase the risk of mammary tumors in mice. However, the exposure of mice heterozygous for the Brca1 or Brca2 gene to DES for 26 weeks, beginning a week before the onset of ductal morphogenesis resulted in inhibited mammary branching structure compared to the wild-type littermates at six months of age (24).
Whereas there are no published reports of viable Brca1 -null mice, the viability of
Brca2 null mice depends on the position of the mutation with more 3í alterations favoring survival. Mice with Brca2 mutations within or immediately 3í of the BRC repeats occasionally survive and succumb to thymic lymphoma at an early age (25,26). Brca2 null mice lacking the terminal exon 27 are largely viable and are susceptible to spontaneous tumor development (McAllister et al., manuscript in preparation). In addition, the females display inhibited ductal morphology in the mammary glands.
Conditional Brca1 -null mice have been generated that inactivate Brca1 specifically in the mammary gland. These mice display an inhibited ductal branching pattern and develop mammary tumors after a year of age (27). Tumor progression is accelerated by crossing these mice onto a p53 heterozygous genetic background. These mouse models may provide a useful model for the study of prevention strategies or therapeutics in high risk populations as well as the general population.
Mutations of the p53 tumor suppressor gene are the most common genetic alteration in human cancer. Women in Li-Fraumini cancer families who inherit mutation in the p53 gene are at increased risk of developing breast cancer, and women and men display increased incidence of cancer at multiple sites including soft tissue sarcomas, osteosarcomas and lymphomas. Gene-targeting and homologous recombination were used to develop mice homozygous for an exon 5 mutation (28). The homozygous null p53 mice developed normally but are highly susceptible to neoplastic development with a 74% tumor incidence by 6 months of age, yet mammary tumors are rarely observed.
Hemizygous p53 mice rarely develop tumors before 9 months of age but the tumors that
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do develop are similar to the spectrum observed in the p53 null mice and include lymphomas, soft tissue sarcomas and osteosarcomas. When MMTV/ Wnt-1 transgenic mice, which develop mammary neoplasias, are crossed onto a p53 -null genetic background they develop mammary tumor at an accelerated rate compared to those mice with a wild-type p53 genetic background. This suggests that p53 defects can contribute to mammary carcinogenesis in mice (29).
Adenomatous polyposis coli ( APC ) is a tumor suppressor gene that when mutated is involved in sporadic and inherited colon cancer and predisposes individuals to the development of hundreds to thousands of colorectal polyps, a subset of which can acquire the ability to progress to carcinomas (30,31). Recent studies have investigated the association between the I1307K APC allele and the development of breast cancer (32,33). The I1307K polymorphism gives rise to an unstable (A) n
in the coding region which enhances the possibility of polymerase slippage during DNA replication. Breast cancer patients who inherited the I1307K allele were twice as likely to carry a mutation in BRCA1 or BRCA2 compared to controls. Thus, it has been suggested that the APC gene may be a low penetrance breast cancer susceptibility gene or perhaps a modifier of the BRCA loci (32,33).
Several Apc mutant mouse models exist that are predisposed to spontaneous intestinal tumors (34,35), similar to that which is observed in humans with inherited APC mutations. The Apc Min mutant mice are highly susceptible to the development of multiple intestinal neoplasms and are susceptible to mammary tumor induction when treated with the alkylating agent N-ethyl-N-nitrosourea (36-38). In another model, Apc 1638N mutant mice display an increase in intestinal tumor multiplicity after irradiation as well as a 15-fold increase in mammary tumor incidence (39). Thus, the mutant Apc genotype can confer high susceptibility to both chemically- and radiation-induced mammary tumorigenesis. However, mammary tumor susceptibility is not altered by Brca2 heterozygosity in the Apc Min mouse model (40).
DMBA rat model of carcinogenesis
The DMBA Sprague Dawley rat tumorigenesis model is a commonly used model for not only understanding the effects of exposure during different windows of mammary gland development but also to evaluate the potential of agents to prevent tumor induction. Notable examples of the effect of exposure during different stages of mammary gland development have been demonstrated and several are described in the following paragraphs.
The chemical exposure of rats in utero can influence mammary tumorigenesis in the adult. The soy isoflavone genistein is a weak estrogen receptor agonist, a tyrosine kinase and angiogenesis inhibitor, and an antioxidant (41). Genistein administration to rats during gestation results in a dose-dependent increase in mammary tumor susceptibility in the adult animal (42). Exposure to the anti-estrogen tamoxifen during fetal development, at days 15 and 20 gestation, increases mammary tumor susceptibility in female offspring treated with DMBA at 45 days of age (42). The tumors
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that developed in the tamoxifen exposed rats were less differentiated and more aggressive than those in the non-tamoxifen exposed group. The administration of
TCDD, a toxic halogenated hydrocarbon, to rats during gestation increases mammary tumor susceptibility in the adult animal (43). Analysis of the ductal epithelium of the
TCDD treated females revealed that the mammary branching structure is less well developed than the controls (43). This less complex mammary ductal branching pattern is similar in morphology to an immature gland sensitive to DNA damaging agents.
Although TCDD mediates its effects through the Ah receptor, it can have effects on endocrine end organs. TCDD exposure in the rat model clearly illustrates that timing can be critical for carcinogen evaluation and may be relevant to human exposure (43-
45). The treatment of adult rats with TCDD inhibits or delays DMBA-induced mammary tumors and can cause regression of existing tumors (44,46). TCDD exposure inhibits ovulation by interfering with follicular rupture and is consistent with the observation that loss of ovarian function is protective for mammary cancers that occur in an endocrine pathway (47).
The window of mammary ductal development extending from birth to puberty appears to be critical for the inhibitory effects of genistein against mammary tumor development. Exposure to dietary genistein from birth until sexual maturity confers dose-dependent protection to DMBA-induced mammary cancer in rats (48). The ductal morphology of the mammary glands isolated from these rats displayed accelerated mammary ductal epithelial differentiation and correlated with protection against mammary tumor development in the rat (48).
The exposure of rats during or after sexual maturation can have very different effects than earlier exposures. Various diets containing soy compounds were fed to rats to identify components that might confer protection to mammary tumor development.
Rats were exposed to diets containing or lacking combinations of isoflavones beginning at 42 weeks of age and one week before DMBA treatment. Rats that began consuming diets supplemented with the isoflavone daidzein, daidzein and genistein, or depleted of both isoflavones developed significantly fewer mammary tumors, but without reduced incidence, than the control group (49). In a similarly designed study, a statistically significant difference in DMBA-induced mammary tumor incidence, multiplicity, or latency was not detected among rats fed soy protein, isoflavone-depleted soy protein, or control diets (50). Similarly, Tamoxifen can inhibit tumor development in the mammary glands of some rats exposed to DMBA or NMU (51).
Numerous animal models exist in which to study mammary carcinogenesis including transgenic rodents, gene-targeted mice, and inbred and outbred rodents. The models are useful for asking questions about the many stages of the carcinogenic process from initiation, through promotion to progression. In addition, the whole animal permits the study of exposures during the different stages of mammary gland growth and development which is important because there is increasing focus on the timing of
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some exposures as it relates to breast cancer susceptibility. While no one model will provide all the answers about breast cancer, the study of models in combination with in vitro studies should increase our understanding of disease and enable us to translate some observations to the clinical setting.
Progress in the identification of risk factors, mechanism of action of environmental exposures, and the consequences of genetic polymorphisms or mutations will require a multidisciplinary approach. Information from animal models in combination with epidemiology, computer modeling, and in vitro studies will contribute to a greater understanding of human breast cancer etiology. In turn, this complementary information that can be used to develop science-based recommendations for reducing the risks of breast cancer in humans.
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