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The finding allows us to understand why a slow-growing breast tumor transforms into a rapidly growing and metastatic one.
Researchers at Baylor College of Medicine, Texas Medical Center, have tracked the progression of breast cancer in an animal model and discovered a pathway that transforms a slow-growing type of cancer known as estrogen receptor (ER). )+/HER2+ in a rapidly growing ER-/HER2+ type that spreads aggressively or metastasizes to other organs.
The study, which appears in the journal 'Proceedings of the National Academy of Sciences', has implications for breast cancer therapy, as it suggests the need to differentiate cancer subtypes according to the path the cells follow. The different pathways could be related to different behavior of the cancer, which should be taken into account to plan treatment appropriately.
"In general, ER-/HER2+ breast cancer is more aggressive than ER+/HER2+ breast cancer, but the ER- type is also heterogeneous in its behavior," explains Dr. Jianming Xu, co-author of this study and professor of the Gordon Cain Chair in Cell Biology in the Department of Molecular and Cellular Biology at Baylor.
"In some patients, ER-/HER2+ cancer responds to therapy and does not come back, but in others, the cancer comes back, grows rapidly, metastasizes aggressively to other organs, and does not respond to treatment, leading to "However, it is not well known what determines the aggressiveness of individual ER-/HER2+ breast cancer."
In the current study, Xu and colleagues investigated the progression of ER+/HER+ and ER-/HER2+ breast cancer cells in a mouse model of the disease. "We wanted to know if the diversity in cancer behavior was related to where the cells came from," said Xu, a member of Baylor's Dan L Duncan Comprehensive Cancer Center.
The researchers applied a novel approach by establishing a mouse model in which they could follow ER+/HER2+ and ER-/HER2+ cancer cells from the beginning of tumor growth to its progression as it became metastatic in living animals.
They tracked all tumor cells arising from ER+ cells with a red fluorescent protein that they could detect throughout progression. The team also compared ER expression, cell proliferation and metastatic capacity between the different subtypes of breast cancer cells that emerged during the process.
The animal model started with equal parts ER+/Her2+ and ER-/HER2+ breast cancer cells. As the cancer grew, the ER-/HER2 cells, which proliferated rapidly but metastasized little, only gave rise to more ER-/HER2+ cells with similar behavior.
On the other hand, although ER+/HER2+ cells produced mostly slow-growing ER+/HER2+ cells, some ER+/HER2+ cancer cells generated cells that had lost their ER. This new population of ER-/HER2+ cancer cells grew rapidly and spread aggressively to other tissues.
"Our study proposes that fast-growing ER-/HER2+ cancer cells can be divided into two subtypes, one that has an ER+ origin, grows rapidly and metastasizes aggressively, and another that has an ER- origin and also grows rapidly but has a less aggressive metastatic behavior," says Xu.
He notes, "Currently all ER-/HER2+ breast cancers are treated in the same way and produce diverse responses. Our findings suggest that different treatments may be necessary. If the observations in our animal model can be validated in humans, we would anticipate that the ER-/HER2+ cancer with an ER+ origin would be very aggressive and should be treated accordingly, he highlights, while ER-/HER2+ cancer that originated from ER- cells would tend to be less metastatic and, therefore, would require a different treatment."
The team also investigated why ER-/HER2+ cancer cells derived from ER+ cells had lost the ER marker and what might have triggered their aggressive metastatic behavior. "We compared ER-/HER2+ cancer cells of ER+ origin, the most aggressive type, with the normal ER+ mammary gland cells from which these cancer cells had originated, at the DNA level," Xu recalls.
"We found that the most aggressive type of cancer, but not the other, had DNA changes that led to shutting down ER expression, which provided an explanation for why the cells had lost their ER," he added.
Xu and his colleagues also tried to explain why the origin of ER-/HER2+ cancer cells would make a difference in the metastatic behavior of the cells. They found that the activation of a key enzyme called MAP kinase was different between the most aggressive and the least aggressive ER-/HER2+ cells, and propose that this difference provides an answer to the nature of their behavior.
"These findings encourage us to investigate whether the discoveries we made in an animal model also apply to patients with breast cancer," said co-correspondent Dr. Bert O'Malley, professor of molecular and cellular biology and chancellor at Baylor. and member of the Dan L Duncan Comprehensive Cancer Center-- Our study supports the concept that cancer progression involves dynamic changes in the cancer cell population. We need to understand these changes so we can design therapies that play with them to improve cancer outcomes. this devastating disease.
