A new study has discovered a mechanism that explains how precancerous cells from early-stage breast tumors travel to other organs and eventually develop into metastasized tumors.

Even though tumors in the breast may be eliminated by surgery or radiation, evidence shows pre-malignant cells can move out of breast tissue at very early stages and embed in other organs to turn cancerous later. This causes the risk of dying from breast cancer to remain the same even after localized tumors in the breast are removed surgically or treated using radiation. Detecting the spread of cancer cells at early stages, before any symptoms arise, therefore, poses a clinical challenge.

Maria Sosa, PhD, an assistant professor of pharmacology and oncology at the Icahn School of Medicine at Mount Sinai, is senior author of this study.

Senior author of the study, Maria Sosa, PhD, an assistant professor of pharmacology and oncology at the Icahn School of Medicine at Mount Sinai said, “The current challenge for the management of treatment of early-stage breast cancer patients—for instance, patients that have the noninvasive lesions such as ductal carcinoma in situ (DCIS)—is that even though local invasive recurrences are reduced after surgery or surgery with radiation, the risk of dying from breast cancer remains the same. This suggests that before detection and removal of the invasive tumor mass some pre-malignant cells disseminated and lodged at other sites waiting for later reactivation.”

Though some biomarkers that flag cancer cells at early stages have been reported, the mechanisms that regulate early dissemination of cancer cells are unclear.

Sosa said, “The identification of an ‘early dissemination signature’ in the breast tissue that could identify patients with risk of developing later relapses, and are therefore candidates for systemic therapy, is crucial to reduce mortality in these patients.”

The new study identifies an orphan nuclear receptor and transcription factor, NR2F1/COUP-TF1, downstream of the oncogene HER2 that serves as a barrier to early dissemination of precancerous cells. The mechanism involves the downregulation NR2F1 that upregulates PRRX1, a master regulator of cellular invasiveness.

The findings were published in the journal Cancer Research, in an article titled, “NR2F1 is a barrier to dissemination of early-evolved mammary cancer cells.”

NR2F1 acts as a barrier to early dissemination and its loss in the mammary epithelium could indicate the presence of early disseminated cancer cells (eDCCs). [Rodriguez-Tirado et al, Cancer Research, 2022]

A small but significant percentage of women with early-stage breast cancer do not progress to invasive metastatic breast cancer, instead, they die after their pre-malignant lesion reemerges into malignancy in other organs like a silent killer. The mechanism uncovered in this study shows how pre-malignant cancer cells acquire mobile and invasive attributes that allow dissemination and colonization in other organs.

The researchers used animal models, pre-malignant breast cancer cells from patients, 3-D cultures, and high-resolution microscopy to investigate how these pre-malignant breast cancer cells disseminate.

The authors noted, “Early cancer cells with low NR2F1 and high PRRX1 staining were observed in DCIS samples.”

Using intravital time-lapse imaging, the team visualized fluorescently tagged early-stage Her2 expressing cancer cells in live animal models to show the decrease or loss of NR2F1 was accompanied by a decrease in a protein called E-cadherin that maintains the integrity and organization of the supportive extracellular matrix, and an increased expression of genes that mobilize fixed cells, a process called epithelial–mesenchymal transition (EMT).

Sosa explained, “This means that the loss or gain in the expressions of these factors (NR2F1low/PRRX1high) in pre-malignant breast cancer cells could be used as potential biomarkers to predict early dissemination events. In the future, and with more clinical studies, we could determine whether the ratio in expression of NR2F1 and PRRX1 can predict for higher risk of relapses in patients with early-stage breast cancer.”

In future studies, Sosa’s team intends to conduct studies on a larger group of patients to uncover the predictive power of the ratio of NR2F1 and PRRX1 expression.

“The clinical significance of pre-malignant cells carrying the NR2F1low/PRRX1high ratio was not reported in this study and needs to be determined by increasing the cohort of DCIS samples and by having access to follow-up studies on overall survival and metastasis-free survival,” said Sosa. “We are also interested in investigating the mechanisms of dormancy and reactivation of early breast cancer cells once they arrive at secondary organs. Knowing how to target early disseminated cancer cells could be critical to prevent metastasis and decrease mortality in patients with early-stage breast cancer.”

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