African American Women and Breast Cancer: What Works?

Walter Price, Dr.P.H., CBCRP Community Initiatives Manager

This attractive, informative poster, which received the award for Best Presentation to a Lay Audience, is an example of the power of a truly collaborative research project. By involving the community in every phase, the entire research project has achieved greater relevancy, accessibility, and success.

The poster highlighted the partnership between Priscilla Banks (Community Co-PI), representing the African American Advisory Committee on Cancer (AAAC); Carol Somkin, research scientist in Kaiser Permanente Oakland’s Division of Research; and Joan Bloom, professor at University of California, Berkeley School of Public Health (Researcher Co-PIs). The AAAC is a group of African American women who are formally involved in many health care issues and advise and interact with health care agencies throughout state and the nation, with a focus in the Bay Area.

The collaboration developed for over a year before the team submitted their concept paper. They started with the very basic question, “Why is it that African American women, while diagnosed less frequently with breast cancer than white women, are more frequently diagnosed with late-stage breast cancer and suffer higher mortality rates than white women?” Through a series of meetings, Ms. Banks worked with Drs. Somkin and Bloom to hone that question into a more granular, achievable line of inquiry, and to develop the team’s research goals and objectives. The AAAC worked with its larger community to ensure that their needs, values, and viewpoints were accurately and equally represented. The team settled on examining healthcare settings and interactions with providers and staff to determine the aspects that promote and inhibit the experience of culturally sensitive care for African American women.

The researchers wrote a first draft of the concept paper (a prerequisite to submitting a CRC application), which was edited and expanded on by AAAC members. Following the concept paper peer review, the AAAC met twice again to discuss and develop a response to the reviewers’ comments. The AAAC also obtained letters of support from the community collaborators, and the partnership wrote and submitted the full application.

Ms. Banks and Drs. Somkin and Bloom continue to participate in all aspects of the design and implementation of the project, from the development of the instruments to the data collection, data analysis, and interpretation. When the project is complete, the partners will participate equally in writing reports and manuscripts. In general, the scientists assist the AAAC to refine the scientific issues and provide research strategies, while the AAAC provide the cultural expertise.

The collaboration between the community and the scientific researchers has enhanced the strength of the research questions, and community’s deep involvement in this project has facilitated the team’s efforts to communicate to a lay audience.
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Studying Breast Cancer Angiogenesis Using a Novel Model System

Laurence Fitzgerald, Ph.D., CBCRP Core Funding Manager

Researchers are continually exploring the use of non-mammalian model systems to study key processes in cancer biology. Because cancer progression involves evolutionarily-conserved biological pathways, such as DNA repair, regulation of the cell cycle, and growth control-signaling pathways, it is often much easier to investigate the underlying genetic and molecular mechanisms using animals that can be manipulated more readily in the laboratory. Konstantin Stoletov, Ph.D., from The Scripps Research Institute, La Jolla, was funded in 2005 through a CBCRP postdoctoral fellowship to use a fish model to explore the initial steps in breast cancer cell invasion and angiogenesis. When Dr. Stoletov presented the early phases of his research at the recent CBCRP symposium, he was selected from over 80 other posters as the winner of the Cornelius Hopper award for Best Innovation.

The story begins with a small fresh water fish, called Zebrafish, which have the unique advantage of being transparent until they are about one month old. Thus, all phases of embryonic development and adult organ structure can be readily observed. These fish mature very rapidly, and they are easier to maintain and experiment on compared to rodent models. Interestingly, Zebrafish can be induced to develop tumors and their morphology and genetic aspects have striking similarities to human cancers. Dr. Stoletov will inject human breast tumor cell lines into Zebrafish and observe the induction of the blood vessel network (angiogenesis) by a technique called “confocal microscopy.” Human tumor cells and fish blood vessels are “labeled” with different colored fluorescent dyes, so they can be directly seen in the living fish by using light of different wavelengths. Thus, tumor growth, cell movements, and progression can be recorded over time in an individual living animal without dissection.

In preliminary studies, Dr. Stoletov demonstrated that the human breast cells can form tumors in Zebrafish, and they will induce the formation of a blood vessel network to allow for their continued growth. A low percentage of the tumors in the fish will spread outside the injection site and kill the animal just like the metastasis events seen in human tumors. In fact, these preliminary studies were the first time sequential images of tumor angiogenesis in a living animal have been generated. The advantage of confocal microscopy is that a series of thin sections can be taken through the tumor-host angiogenic tissue and then used to reconstruct a three-dimensional tumor structure. In terms of the molecular events regulating angiogenesis, the fish appear to be remarkably similar to humans, at least for the key growth-promoting genes, such as VEGF.

Of course, one could ask, “this is interesting, but what experiments can be performed that are relevant to human breast cancer?” First, the Zebrafish system is ideal for studying the earliest movement of cancer cells towards host endothelial cells as the first step in acquiring a blood supply. Little is known about these processes in human cancer, so we lack insight on how to validate drug targets for treating or preventing early cancers. Second, a family of small signaling proteins, called Rho GTPases, can be studied in this system. Rho proteins represent a related family of small GTPases that regulate the cell’s internal actin cytoskeleton. Consequently the most prominent roles for Rho-GTPases include control of cell shape, cell division, and motility. Dr. Stoletov is specifically interested in RhoC, and his Zebrafish system will allow him to modulate the levels of this protein when present in the human tumor xenograft. RhoC gene is overexpressed in a rare, but highly invasive and angiogenic form of breast cancer, called inflammatory breast cancer (IBC). Dr. Stoletov believes that his model system will enable him to uncover the molecular mechanisms activated by RhoC that render IBC so aggressive. Thus, Dr. Stoletov’s innovative Zebrafish model system is poised to shed new light on how RhoC is involved in breast cancer cell movements, induction of angiogenesis, and metastasis.

Dr. Stoletov received his undergraduate training in Russia and completed his graduate work at Albert Einstein College of Medicine in New York. Since 2003 he has been a postdoctoral fellow in the laboratory of Richard Klemke, Ph.D., at Scripps. He is applying an excellent background in angiogenesis and cell motility under the mentorship of Dr. Klemke and in collaboration with other faculty at Scripps to enter the field of breast cancer research.
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A Second Look at Estrogen

Katherine McKenzie, Ph.D., CBCRP External Relations Manager

Satyabrata Nandi, Ph.D., of University of California, Berkeley, presented a poster addressing one of the pivotal questions in breast cancer research today. How can we prevent breast cancer from ever developing? One way to answer this question is to learn which behaviors or physiologic characteristics protect women from developing breast cancer and mimic those conditions in susceptible women.

It has long been observed that a full-term pregnancy before the age of 20 reduces the risk of developing breast cancer by 50 percent. Something about pregnancy causes either changes in the breast or factors affecting the breast that result in protection from cancer. During pregnancy the levels of the hormones estrogen and progesterone are elevated, affecting both the breast cells and the balance of other hormones in the body. Dr. Nandi undertook a study to determine whether it was the hormonal changes or the changes in the breast tissue that was responsible for reducing the risk of developing breast cancer. Armed with this information, he could develop a way prevent breast cancer by mimicking natural processes.

Dr. Nandi realized that trying to answer this question in humans would be difficult because there are such wide variations between individuals and even within the same women at different stages of maturity and menstrual cycle. Instead, he decided to tackle this question by investigating it in rodents, which also are protected from developing breast tumors by pregnancy during adolescence.

Dr. Nandi gave pregnancy levels of estrogen or estrogen and progesterone to adolescent rats for two to four weeks, even though giving estrogen is counter-intuitive because a body of data indicates that higher lifetime exposures to estrogen correlate with a higher risk of developing breast cancer. Estrogen is a complicated hormone and has many effects throughout the body. The time of life when exposed to estrogen may actually be the determinant of whether estrogen is protective or promotes cancer. Indeed, Dr. Nandi found that estrogen or estrogen and progesterone treatment in adolescent rats protected them from developing mammary tumors long after the treatment ended.

Changes at the cell level were not the reason for this protection. Cells can be induced to mature through non-estrogenic means, but while they look like the cells that were caused to mature by using estrogen, they do not behave the same way. In animals that received the estrogen treatment, prolactin and growth hormone (which contribute to the tumor growth) were permanently reduced and their mammary glands were protected from developing tumors. This precisely mimicked the hormonal changes and protection from tumor development that occurs due to full term pregnancy. Non-estrogenic treatments did not change the balance of these hormones, nor did they protect the mammary gland from developing tumors.

The protective effect of short term estrogen or short-term estrogen and progesterone treatment is as effective as ovariectomy or long term treatment with tamoxifen in rats. Moreover, no side effects in fertility, body weight, or other cancers were observed with the short-term treatments. If this paradigm holds up for humans, then it may be possible to develop a safe, effective, and universally affordable prevention strategy for breast cancer that would not require long-term hormone treatments.