Why I
Joined GGCP

The road that brought me to UC Davis has been a long and winding one. It has taken me from The Netherlands to Ivory Coast, Colorado, North Carolina, and now California, with a brief stay in Virginia.

I graduated with a major in zoology and got an MS in reproductive physiology and primate behavior from the University of Utrecht in The Netherlands; subsequently, I obtained my veterinary degree from Colorado State University. I worked for three years in North Carolina with a wide variety of species, from mice to horses and from binturongs to snow leopards.

During a short internship at the CRC (Smithsonian Institution in Virginia), I became interested in reproduction and its spin-off, contraception, as tools for conservation of endangered species for humane and effective population management of animals in captivity, as well as for controlling wildlife populations, whether of naturally occurring species (e.g., white tail deer) or introduced ones (e.g., feral cats) in an environment that has been unbalanced by humans.

The work of Dr. Linda Munson monitoring the side effects of various contraceptives caught my attention because of its scope and depth with such a wide variety of species. The present project focuses on the effects of progestins on the feline mammary and endometrial epithelium and uses a combination of in vitro (cell culture), in vivo (domestic cat), and retrospective (exotic felid archived reproductive tissues) work. This research combines aspects of comparative pathology, reproduction/contraception, and wildlife management and involves research at the cellular and whole-animal level, with its results potentially affecting animals at the population level.

It is becoming increasingly clear that many pollutants can have an impact on human as well as animal reproduction, either directly because of their steroidogenic effects or because these toxins are carcinogens. Toxins found in the environment have an impact on all the creatures that live in it; however, the mechanism and extent of this impact is not always well understood.

In addition to environmental exposure, hormone manipulation has been used in veterinary medicine to enhance reproduction (cattle, mares, wildlilfe) and to suppress reproduction (cats and dogs). Use of these hormones has been associated in cats and dogs with a variety of adverse effects. Although in the U.S. many pet cats are spayed, the need for contraception and estrus suppression is still present in some cases. Breeding and management programs for captive endangered nondomestic felid species also need effective, safe contraception—It may be undesirable to have a particular animal reproduce each year, but its genes may be important enough that it may be desirable for it to reproduce later, making reversibility key. Additionally, free-ranging animal populations may also need to be controlled (e.g., feral cats, pigs, deer, etc.) Progestin-based contraceptives are among the most reliable and effective used in felids, domestic and nondomestic; however, they have been associated with side effects.

One important side effect reported with the use of progestin-based contraceptives is the potential for mammary gland cancer, an important disease in veterinary medicine that occurs naturally in felids, like in other species. Among female domestic cats, mammary gland cancer is the third most common malignancy and accounts for 17 percent of all neoplasms. Mammary cancer development has been associated with exposure to steroid hormones in many species. The risk of developing mammary cancer in intact female cats is seven times higher than in age-matched controls that were ovariohysterectomized before one year of age. Young female cats may develop mammary hyperplasia during their first natural cycle. Exposure to exogenous progestins has been linked to mammary cancer development in domestic cats and nondomestic felids. Exogenous progestins have been widely used in domestic cats to prevent or suppress estrus, modify behavior, or treat dermatologic conditions and in nondomestic felids to prevent pregnancy. The fact that administration of synthetic progestins is associated with mammary hyperplasia in domestic cats, including males, and that administration of antiprogestins to cats reverses hyperplasia suggests a role for progestins in the process. On the other hand, mammary gland cancer does not develop in all intact cats nor in all cats that are administered progestins. This in turn suggests that progestins, including endogenous progesterone, may act to promote more than cause cancer and that synthetic progestins may have a similar effect.

Interestingly, there are a number of similarities between human breast cancer and feline mammary cancer: a) there seems to be a link between the development of mammary gland cancer and a cumulative exposure to progestins, b) mammary neoplasia is usually malignant (invasive), and c) it seems to arise from the epithelium of the gland.

The exact role of progestins in promoting mammary cancer, however, remains unclear. Two important factors that regulate cell population growth are proliferation and apoptosis (programmed cell death). Gaining independence of signals that regulate cell population size is a necessary step in oncogenesis (development of cancer). Disregulation of both cell proliferation and apoptosis often occurs through the accumulation of mutations in genes such as tumor-suppressor and/or proto-oncogenes. Rapidly dividing tissues, such as the mammary gland under hormonal stimulation, are fertile soil for the development of mutations.

This project aims to define the effects of progestins in terms of proliferation and apoptosis on feline mammary epithelium as well as on feline endometrial epithelium in vitro and in vivo. One important aspect of this project is that it focuses on how cancer may be promoted by using normal rather than neoplastic cells and tissue. Another goal is to determine if there are differences among the various synthetic progestins in terms of their effects and the degree of their effects. By knowing more about how progestins cause side effects, we will be better able to design safer but still effective contraceptives.

TUNEL stain of feline mammary epithelial cells