Breast cancers that emerge after a woman gives birth are significantly more deadly. Those diagnosed within five years of childbirth are about three times more likely to spread and give rise to life-threatening metastatic tumors. Researchers now are closing in on the reasons why.
Scientists at OHSU have discovered how the liver – one of the most common sites of breast cancer metastasis – becomes vulnerable to tumor invasion after childbirth. Using rodent models, they’ve shown that as the liver recovers from the demands of pregnancy and lactation it becomes an inviting landing spot for escaping cancer cells to take root and grow.
Image: detail from a painting by Albert Neuhuys (Rijksmuseum)And the same process appears likely to occur in women. The researchers dug into the details of more than 500 cases of young women’s breast cancer and found a liver-specific increase in metastasis among those diagnosed within five years of giving birth. If confirmed by more direct evidence, the authors say their findings could help physicians choose more effective treatments for young mothers diagnosed with breast cancer. The researchers reported the findings in the February issue of Cancer Discovery.
It’s been known for some time that changes within mammary tissue after lactation promote the early stages of breast cancer metastasis, when tumor cells become mobile. “But we didn’t know if there were reciprocal processes in sites where breast cancer metastasizes,” says lead study author Erica Goddard, a doctoral student working with Pepper Schedin, Ph.D., a professor in the Department of Cell, Developmental & Cancer Biology at OHSU.
This group found that the much greater risk of metastatic disease in the post-partum period is independent of tumor stage or tumor mutations known to increase aggressiveness. That observation prompted Schedin, Goddard and colleagues to consider the influence of whole-body changes after pregnancy and lactation.
Women with breast cancer liver metastasis have a median survival of about four months.
They focused on the liver because it undergoes sweeping changes in size during the female reproductive cycle. The liver expands during pregnancy and lactation, specifically to boost the production of the sugar glucose that’s shuttled to mammary glands for milk production. The researchers hypothesized that the liver must shrink after pregnancy and nursing, and that the shrinking process, or involution, creates a pro-tumor environment.
Before this study, it was unknown how the liver returns to its baseline state after weaning. Goddard, Schedin and co-authors found that after weaning, the maternal rat liver shrinks in size due to an orchestrated pruning of cells – programed cell death – and remodeling of the stroma, the matrix of connective tissue and blood vessels surrounding liver cells.
“In the mammary gland, involution is a cell-death mediated processes,” Schedin says. “That’s what triggers stromal remodeling and a pro-tumor microenvironment. And while it was known that the liver increased in size with pregnancy and lactation, not everybody agreed that it was based on a proliferation phase and not cellular hypertrophy. Further, how the liver returned to baseline was unknown and thought to be due to cells going from fat to thin – not programmed cell death.”
Along with the pruning of liver cells and remodeling of stroma, the researchers found that immune cells infiltrate the involuting liver, consistent with the need to clear away dead cells and suppress immune system reactions. “Those are hallmarks of a wound healing-like process,” Goddard says, “and as a consequence, the liver is programmed to a pro-metastatic micro-environment.”
To test this directly, the researchers injected breast cancer cells into the blood stream of female mice, half that had not given birth and half that had recently weaned a litter. There was no difference between groups in the occurrence of tumors in the lung, bone and brain. But liver tumors arose earlier and significantly more frequently in the post-weaning group.
For further evidence, the researchers delivered breast cancer cells directly into the livers of mice to compare survival and growth of tumors under three different conditions: soon after weaning while liver involution is taking place, four weeks after weaning when the liver is back to its baseline condition, and in never-pregnant animals. Triple the number of tumors grew in the immediate post-weaning group than in both the fully recovered group and the never-pregnant group, suggesting that the vulnerability to metastasis is temporary and limited to the period of active liver involution.
For new mothers with breast cancer,
the findings could lead to changes in treatment decisions
The biology is not so easily studied in human subjects, but the researchers were able to glean support from a detailed study including 564 women with breast cancer, all diagnosed at age 45 or younger. After laboriously reviewing medical records, Goddard and co-authors were able to compare the rate of metastatic tumors in postpartum women with that of women who hadn’t given birth. Liver metastases were 3.6 times more frequent in the post-partum women, those diagnosed within 5 years of giving birth. The greater risk of liver metastasis persisted after adjusting for tumor biologic subtype, patient age, and year of diagnosis (which helps take into account treatment advances over time).
The increase in metastatic tumors in women with breast cancer appears to be liver specific. As in the rodent studies, the researchers did not find significant differences in frequency of cancers spreading to bone, lung or brain – the other common sites of breast cancer metastasis.
Women with breast cancer liver metastasis have a median survival of about four months, compared with five years for women with bone-only metastasis. And that raises the possibility “that differences in site-specific metastasis contribute to the poor survival rates of women diagnosed postpartum,” the researchers note in the conclusion of their paper.
“If validated our finding that postpartum patients experience an increased risk for liver metastasis could lead to changes in treatment decisions in this vulnerable population of young mothers diagnosed with breast cancer.”
The Rodent Liver Undergoes Weaning-Induced Involution and Supports Breast Cancer Metastasis by Erica T. Goddard, Ryan C. Hill, Travis Nemkov, Angelo D’Alessandro, Kirk C. Hansen, Ori Maller, Solange Mongoue-Tchokote, Motomi Mori, Ann H. Partridge, Virginia F. Borges and Pepper Schedin. Cancer Discovery (February 2017)