Daily Archives: October 23, 2017

Of Mice and Mammaries, Part 3: Modelling Human Breast Cancer

In light of Breast Cancer Awareness Month, Justin Varholick traces how mice have helped breast cancer research over the past century. In the third post of this 4-part series, we look at advances made from the 1970s to present time and how mice are being used as a model for humans.

Over the past two weeks, in Parts 1 and 2 of this series, we discussed how scientists discovered mammary tumors in mice, and how some mice have the mouse mammary tumor virus (MMTV) – which spreads cancer to offspring through the mother’s milk. After scientists found it difficult to grow MMTV in a petri dish, they realized that they had to continue studying mammary tumors in the mouse itself. This week we will focus on how scientists validated – and are continuing to validate – mammary tumors in mice as a model for understanding human breast cancer.

Validating mice as a model for humans is not an easy task. Scientists must be able to show that the cause, development, or progression of the tumors are similar between mice and humans. However, human breast cancer is often caused by many different factors and does not always develop or metastasize consistently. Thus, scientists can only model certain aspects of breast cancer. For example, they might be able to model a cause of cancer but not the development or progression.

1975 to Present — Stem cells and pre-cancer stages

Stem cells of mammary tumors have become a valuable tool throughout the years because they allow scientists to study cells that may one day become cancerous, and determine ways to prevent them from becoming cancerous.

Original image by Science Magazine

Stem cells of mammary tumors were first identified in 1975 by Dr. Barry Pierce. Since this discovery, scientists have isolated these stem cells and tested different factors to prevent the stem cells from becoming cancerous. Unfortunately, no major findings to definitely prevent stem cells from becoming cancerous have been found.

Although no major findings have been found, stem cell research is very promising. Mice with mammary tumors that are caused by pre-cancerous stem cells often have tumors that are similar in shape to those found in humans. Thus, although we do not yet understand which factors may directly cause stem cells to become cancerous, the development and progression of the tumors in mice and humans are similar – making them a good model for research.

1980s to Present — Genetically Engineered Mice

While research on stem cells was underway, some scientists began exploring the idea of genetically engineering mice to have mammary tumors. This research would help scientists understand which genes are associated with mammary tumors, and also provide scientists with mice that reliably have mammary tumors from different genetic causes.

Genetically Engineered Mice

Because much research was already done on MMTV, the first genetically engineered (GE) mice were those that were genetically engineered to have MMTV. Unfortunately, GE mice with MMTV genes could not be used to understand human breast cancer. One reason was because human breast cancer is not caused by a virus. The second reason is because the types of tumors that develop from MMTV differ in cellular shape and structure compared to human tumors. Because mammary tumors in GE mice with MMTV are caused by different factors, and develop and progress differently, this makes them a poor model for research.

Although these first GE mice cannot be used as models, their creation helped scientists make different GE mice with tumors almost indistinguishable from human tumors. To make these GE mice, scientists inserted genes into mice that were associated with breast cancer in humans. These genes were erbB2 and myc. Because these genes caused mammary tumors in both humans and mice, this made them a good model for future research.

Unfortunately, breast cancer in humans is not always caused by genes. Some breast cancer is caused by abnormal hormone levels, carcinogens, and other factors that we do not yet understand. Also, because breast cancer has different causes this also means it has different pathways of development.

These differing factors make studying breast cancer difficult. But by studying more and more about mammary tumors in mice we may be able to build better models that will one day lead to better treatment options.

Justin Varholick

To be continued…

Tune in next week to learn which treatments scientists have discovered for humans by using mice as models. I will also cover the potential future of breast cancer research – patient derived xenografts.

References:

  1. Cardiff R, Kenney N. (2011). A compendium of the mouse mammary tumor biologist: From the initial observations in the house mouse to the development of genetically engineered mice. Cold Spring Harb Perspect Biol. 36(6).
  2. Medina D. (2010). Of Mice and Women: A Short History of Mouse Mammary Cancer Research with an Emphasis on the Paradigms Inspired by the Transplantation Method. Cold Spring Harb Perspect Biol. 2(10).
  3. Cardiff R, Couto S, Bolon B. (2011). Three interrelated themes in current breast cancer research: gene addiction, phenotypic plasticity, and cancer stem cells. Breast Cancer Research. 13(5).