Breast cancer affects about 10% of women in their lifetime and is a serious medical and social burden. Fewer treatment options are available for breast cancers that lack estrogen receptors and therefore do not respond to hormone therapy. Breast tumors that lack not only ER-alpha, but also the EGFR tyrosine kinase receptor and the progesterone receptor, are particularly difficult to treat. They resist to conventional drugs and they are labeled “triple negative”. Now researchers at the Karolinska Institutet in Sweden have identified a protein that protects against breast cancer growth and may be linked to a better prognosis in patients. The findings may contribute to the development of new therapies for difficult-to-treat forms of breast cancer. Scientists have identified a new mechanism by which the ubiquitous GIT1 protein regulates the Notch signaling, which affects the onset and growth of ER-negative breast cancer.
Notch signaling is an evolutionarily conserved cell-cell communication mechanism, which regulates the formation of organs in embryogenesis, decisions on cell fate in most organs of the body and at different stages during cell development. Overactive Notch reporting in breast cancer patients has previously been linked to a worse prognosis. Studies on cancer cells from breast cancer patients showed that high levels of GIT1 inhibited Notch signaling and suppressing tumor growth, while low levels of GIT1 improved tumor growth. Patients’ ER-negative breast cancers had lower levels of GIT1 than ER-positive breast cancers. Moreover, ER-negative breast cancer patients with high levels of GIT1 had a better prognosis than those with low levels. This protein indeed, is known to interacts with some compontents of the cytoskeleton and may promote propension to metastatization.
Another very recent research from the University of South Australia has found a connection between aggressive breast cancer cells and cell surface double protein complexes CXCR4-CCR7. Research shows a direct relationship between the number of these associations and the severity of the disease. This is the first time that this protein interaction has been observed in both animal and human cells. On their own, the CXCR4 and CCR7 proteins are found in many cell types, including breast cancer cells. But it has been observed that in the most invasive and metastatic breast cancer cells, they are bound to each other, to provide specific signals that make these cells grow and move rapidly. And it is not the only cytokine-dependent system that appears to be involved in the biology of breast cancer. C-C Motif Chemokine Ligand 18 (CCL18) and its partners also appear to participate.
This ligand is expressed in many human cancers, appears to have many unrelated receptors, and is also present in breast cancer tissue. In the tumor tissue niche, the macrophages present synthesize CCL18 and its overexpression correlates with reduced patient survival in multiple tumors. Although multiple receptors are reported for CCL18 including the CC chemokine receptor type 3 (CCR3), type 6 (CCR6), type 8 (CCR8) and the membrane estrogen receptor (GPER1), the membrane protein PITPNM3 is currently considered its predominant receptor. But chemokine ligand 5 (CCL5) is also one of the cytokines highly correlated with invasive and metastatic stages of breast cancer. A previous study suggested the prognostic value of CCL5 expression in luminal breast cancer B (HER2-negative). The latest research proves that the overexpression of CCL5 influences the M2 differentiation of macrophages;
Lab researchers indicated that the elimination of CCR5, a CCL5 receptor in macrophages, inhibited the effect of inducer molecules in promoting their differentiation. Then CCL5 is produced by breast cancer cells to polarize the macrophages, thus conditioning the immune response against them. In addition to growth factors and cytokines, therefore, chemokines also play an ever-increasing role in the context of cancer biology, including breast cancer. Scientists think that this is precisely one of the reasons why there is a lot of heterogeneity in the immune response, in the response to drugs and immunotherapy against breast cancer. Therefore, only a thorough knowledge of these mechanisms can provide the basis for future more targeted therapies.
- edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Aravind A et al. J Cell Commun Signal 2022;16(2):293.
Zhang S et al. Nature Commun 2022 Mar 22; 13:1537.
Zhu YY, Zhao YC et al. Gene 2022 Feb 20; 812:146100.
Poltavets V et al. Life (Basel). 2021 Oct 7; 11(10):1049.
Dott. Gianfrancesco Cormaci
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