Having dense breasts - areas that show up light on a mammogram - is strongly associated with increased breast cancer risk, but “why” remains to be answered. Now, by examining dense and non-dense tissue taken from the breasts of healthy volunteers, researchers from Mayo Clinic have found several potential links.

In two studies being presented simultaneously in poster form at the Cancer Therapy & Research Center-American Association for Cancer Research (CTRC-AACR) San Antonio Breast Cancer Symposium, the researchers report that dense breast tissue contains more cells believed to give rise to breast cancer, compared to non-dense tissue. "We found a dramatic difference in tissue composition between dense and non-dense tissue in the breast," says Karthik Ghosh, M.D., a Mayo Clinic breast cancer researcher and physician who led one study.

In a second study, researchers also found that dense breast tissue has more aromatase enzyme than non-dense tissue. This is significant because aromatase helps convert androgen hormones into estrogen, and estrogen is important in breast cancer development, says that study's lead investigator, Celine Vachon, Ph.D.

"If aromatase is differentially expressed in dense and non-dense breast tissue, this could provide one mechanism by which density may increase breast cancer risk," Dr. Vachon says.

The researchers say these findings are unique because these studies are the first to examine areas of both dense and non-dense tissue taken from the same breast in healthy volunteers. Examination of healthy women is important, Dr. Ghosh says, because most prior studies of breast density have looked at tissue taken from women with known breast disease.

Sixty women, age 40 to 85, allowed Mayo Clinic researchers to take eight core-needle biopsies from their breasts; none had a history of breast cancer.

Dr. Ghosh and her team examined the biopsies to determine the percentage of epithelium tissue, stroma, and fat content in each. The epithelium is primarily composed of milk glands and ductal cells, and stroma is the connective tissue that supports epithelial cells. Dr. Vachon and her colleagues looked at aromatase expression within cells in both dense and non-dense tissue.

Results are now available from more than half of the participants who donated biopsy tissue. Dr. Ghosh found that areas of density contained much more epithelium (6 percent) and stroma (64 percent) and much less fat (30 percent), compared to non-dense tissue that contained less than 1 percent epithelium, about 20 percent stroma, and almost 80 percent fat. "This shows us that both the epithelium and stroma contribute to density, and suggests that the large difference in stroma content in dense breast tissue may play a significant role in breast cancer risk," Dr. Ghosh says.

She also looked at lobular involution, a decrease in the size and number of milk ducts that has been associated with decreased breast cancer risk, and found that 85 percent of non-dense tissue had complete involution compared to 35 percent of dense tissue.

Dr. Vachon and her team examined expression of aromatase in the biopsy samples and found that the stromal cells in dense breast tissue had more aromatase and intensity of expression in dense tissue, compared to non-dense. They say these findings may help explain why women with greater proportion of dense breast tissue are at greater risk for breast cancer than women with little or no density.

"These are initial findings from one of the first attempts to study breast density at the level of healthy tissue. It doesn't explain everything yet, but is providing really valuable insights," says Dr. Ghosh, who established the patient resource for both studies.

Drs. Ghosh and Vachon are finishing their analysis of the initial 60 volunteers, and they are also enrolling more participants in order to validate and expand their findings. "No one knows why density increases breast cancer risk, but we are attempting to connect the dots," Dr. Vachon says.

These studies were funded by the Mayo Clinic Breast Cancer Specialized Programs of Research Excellence (SPORE) grant, and a National Institutes of Health (NIH) career development award.

About Breast Cancer

• Ductal carcinoma in situ (DCIS): This is the most common type of non-invasive breast cancer (85 - 90% of all cases). DCIS means that the cancer is only in the ducts. It has not spread through the walls of the ducts into the tissue of the breast. Nearly all women with cancer at this stage can be cured. Often the best way to find DCIS early is with a mammogram.
• Lobular carcinoma in situ (LCIS): This condition which occurs in approximately 8% of all cases, begins in the milk-making glands but does not go through the wall of the lobules. Although not a true cancer, having LCIS increases a woman's risk of getting cancer later. For this reason, it's important that women with LCIS to follow the screening guidelines for breast cancer.

• Inflammatory breast cancer (IBC): This uncommon type of invasive breast cancer accounts for about 1% to 3% of all breast cancers. Usually there is no single lump or tumor. Instead, inflammatory breast cancer (IBC) makes the skin of the breast look red and feel warm. It also gives the skin a thick, pitted appearance that looks a lot like an orange peel. Doctors now know that these changes are not caused by inflammation or infection, but by cancer cells blocking lymph vessels in the skin. The breast may become larger, firmer, tender, or itchy. IBC is often mistaken for an infection in its early stages. Because there is no defined lump, it may not appear on a mammogram, which may make it even harder to catch it early. It usually has a higher chance of spreading and a worse outlook than invasive ductal or lobular cancer.
• Paget's disease of the nipple. Paget's disease of the nipple or breast is a rare type of breast cancer, which can occur in women and men. It shows up in and around the nipple, and usually signals the presence of breast cancer beneath the skin. Most cases are found in menopausal women, but can also appear in women that are as young as 20.  Early stages symptoms include redness, scaly and flaky, and  mild irritation of  nipple skin. Advanced stages may include: tingling in nipple skin, very sensitive skin on the nipple, burning or painful nipple skin, ooze or bloody discharge from the nipple (not milk), itchiness that doesn't respond to creams, nipple retraction (pulls into the breast), scaly rash on areola skin, and/or breast lump beneath the affected skin.

• a lump or a thickening in the breast or in the armpit. Note Most breast lumps are benign (be-nine); that is, they are not cancer. Benign breast tumors are abnormal growths, but they do not spread outside of the breast and they are not life threatening. But some benign breast lumps can increase a woman's risk of getting breast cancer. Most lumps turn out to be caused by fibrocystic (fi-bro-sis-tik) changes. Cysts are fluid-filled sacs. Fibrosis is the formation of scar-like tissue. Such changes can cause breast swelling and pain. The breasts may feel lumpy, and sometimes there is a clear or slightly cloudy nipple discharge.
• a change of size or shape of the mature breast
• fluid (not milk) leaking from the nipple
• a change of size or shape of the nipple
• a change of color or texture of the nipple or the areola, or of the skin of the breast itself (dimples, puckers, rash)
• a discharge from the breast

The 2008 San Antonio Breast Cancer Symposium (SABCS)