Australasian Science: Australia's authority on science since 1938

The Breast Exposed

mammogram

Why does the breast so commonly get cancer when it is not a tissue that is particularly exposed to the environmental agents that increase cancer risk in other major organs?

By Wendy Ingman

Why is the breast so prone to cancer?

The skin and lungs are two tissues that are frequently bombarded with cancer-initiating factors, such as ultraviolet rays from the sun and smoke and pollutants in the air we breathe. Yet breast cancer is the most common type of cancer in Australian women, affecting one in eight before the age of 85. It is more common than skin melanoma and lung cancer.

Why, then, does the breast so commonly get cancer when it is not a tissue that is particularly exposed to the environmental agents that increase cancer risk in other major organs? Is there something unique about this tissue that makes it particularly susceptible?

The breast undergoes cellular changes over the course of the monthly menstrual cycle, and and these changes affect cancer susceptibility. Rising levels of the hormones oestrogen and progesterone occur immediately after the egg is released from the ovary, and these hormones cause the breast cells to divide and change to accommodate further development if pregnancy occurs.

If the woman becomes pregnant, the cells in the breast continue to develop and become the milk-producing structures required to feed a newborn baby. But if pregnancy does not occur there is a drop in progesterone, which triggers the death of the newly developed breast cells. This occurs at the same time women have their period.

Then the cycle starts again, and continues every month until menopause, unless the woman becomes pregnant.

We have discovered that immune system cells known as macrophages have a role to play in the normal function of the breast over the course of the menstrual cycle. We used genetically modified mice whose macrophages could be selectively removed to study the role of these cells in the breast. It turns out that macrophages help the breast cells to divide and change as hormone levels rise, and gobble up the dying cells when hormone levels drop.

But at certain stages in the menstrual cycle, our mouse studies suggest that these macrophages may open up a window of breast cancer risk. The window of risk is most evident around the time when progesterone levels drop, which is the phase of the cycle when women have their period. At this stage of their menstrual cycle, immune defences in the breast tissue are down, and women could be more susceptible to initiating factors that can lead to breast cancer.

Macrophages are important cells of the immune system, and usually help to protect our body from cancer. But we have found that when progesterone levels drop, macrophages stop displaying a protein on their cell surface known as NKG2D, which detects cells that have undergone DNA damage. At the same time, macrophages increase the abundance of another protein called Macrophage Scavenger Receptor 1, which helps the macrophage gobble up dying cells.

So when progesterone drops, macrophages concentrate their efforts on clearing up the dying breast cells and lose focus on detecting cancerous cells. It’s a sort of Jekyll-and-Hyde scenario: we need the macrophages to do their job so that the breast can function normally, but at the same time they may be giving cancerous cells the chance to survive.

Puberty, Pregnancy and Lactation

The breast is a unique organ because it goes through the majority of its development a long time after birth. The major phases of breast development occur during puberty, when the cellular structures develop to maturity, and pregnancy, when the cells become altered to enable milk production during lactation.

When the newborn is weaned and lactation is no longer required there is a process called “involution”, where all the cells that were required to support milk production die and are removed. At this stage the breast tissue is remodelled back to its non-pregnant state. All this development commences again with the onset of another pregnancy.

Milk is an essential part of the life cycle of all mammals. In fact, provision of milk to newborns from the breast is one of the defining features of mammals. Milk provides both nutrition and immunological protection to the newborn. Having freshly come from a protected environment inside the mother’s womb, where all the required nutrients were provided, milk is specially designed to help the newborn in those first few weeks, months and in some species, years.

Therefore, it is critically important to the survival of mammalian species that the function of the mammary gland is protected so that milk can be produced to nurture the next generation. However, the extensive changes that occur in the breast pose some unique immunological challenges.

The immune system is programmed to maintain the status quo by mounting attacks against invading bacteria and viruses, and preventing rogue cells from developing into tumours. So when a tissue undergoes such extensive changes as the breast does, the immune system must develop particular strategies to allow this to happen. If the immune system accidentally triggered an attack against the body’s own breast cells, lactation could be compromised.

Menstrual Cycling and Breast Cancer Risk

It was back in the 18th century that an Italian doctor called Bernardino Ramazzini noted that nuns seemed to be particularly at risk of developing breast cancer compared with the married women in the community. His first thought was that perhaps sexual activity helped to protect the breast from cancer.

However, centuries of careful studies dissected out the factors most important to breast cancer risk, and revealed that it is actually child-bearing and other factors related to reproductive history that affect women’s breast cancer risk. We now know that not having children, not breastfeeding, going through puberty at an early age or menopause at a late age all increase a woman’s risk of developing breast cancer. And something that all these factors have in common is that they all increase the total number of years of menstrual cycles a woman goes through in her lifetime.

The effect of these reproduction-associated factors on breast cancer risk is quite dramatic. For example, a young girl who goes through puberty at the age of 15 will have a 20% reduced risk, for her entire lifetime, of developing breast cancer compared with a girl who goes through puberty at age 11. Similarly, a woman who goes through menopause in her early forties has a reduced risk of nearly 30% compared with a woman who goes through menopause in her early fifties.

But how do reproduction-associated factors like the age a girl goes through puberty affect breast cancer risk, when a lot of women don’t develop breast cancer until they are much older – sometimes long after they have stopped menstrual cycling completely?

The answer lies in the complex developmental nature of the tumour itself. Initiation of breast cancer can be by external factors such as exposure to carcinogens that cause DNA damage, or internal factors such as the hormones that stimulate cell division.

Cells sometimes make mistakes in replicating or repairing the DNA, and gene mutations arise. These initiating factors start cells on the pathway to cancer, but fortunately most cells don’t complete the journey. A single cell must be hit by multiple gene mutations in order to grow into a tumour. Mutations of particular genes enable the cell to keep dividing and survive long after it should have become non-functional, and to evade the body’s mechanisms to shut it down.

The likelihood of DNA mutations affecting all these genes in a single cell is actually very low and can take years to accumulate. Hence these early initiating factors can occur in young women but not show up as cancer until many years later.

When it comes to cancer there is also an important element of luck. DNA mutations affect genes quite randomly, so in some cases tumour development can happen relatively quickly. Unfortunately there is a significant number of women in their twenties and thirties who develop breast cancer.

It is very difficult to alter the impact of reproduction-associated risk factors for breast cancer. Supporting women to increase the duration of breastfeeding will help to reduce their risk of breast cancer, but other factors such as the number of children women have is a personal choice made by each family.

Women today have fewer children compared with women in the 18th century, when Bernardino Ramazzini made his first discoveries about the relationship between having children and the risk of breast cancer. Back then, infant and child mortality rates were very high, and couples had large families to ensure at least a few survived to become parents themselves. Thanks to the wonderful advances in modern medicine, this is no longer the case.

Puberty is also a very complex process, and we do not yet understand why some girls go through puberty earlier than others. By investigating the underlying biology that causes menstrual cycling to affect breast cancer susceptibility, we hope to figure out how to close the window of cancer risk so that less women suffer from this deadly and common disease.

Wendy Ingman is Head of the Breast Biology and Cancer Unit at The University of Adelaide.