Breast cancer occurs when there is a disruption in the normal cell reproduction resulting in abnormal mutated cells in the mammary gland. These mutated cells are characterized by the uncontrollable growth and ability to proliferate on top of other cells. Devoid of the characteristics of normal cells, cancer cells tend to replicate rapidly causing a tumor. The most common type of breast cancer starts in the breast lobules or ducts. Invasive or non-invasive carcinoma is differentiated depending on whether the malignant cells stay on the lining of the breast structure or spread outside the lobules and the ducts. When the breast cancer is limited to the breast or nearby lymph node region, it is called localized or early stage. Once the cancer cells metastasize, it would indicate a more advanced stage of cancer. Breast cancer metastasis occurs when the malignant cells break off from the primary tumor and move to other body parts. The complex linkages of lobules and milk ducts; lymphatics and lymph nodes; and artery and veins in the breast play a role in the mechanism of malignant breast cell metastasis. A closer view of the sequence of events occurring during metastasis can be a key in metastatic breast cancer progression prediction and treatment.
The first phase of metastasis is the invasion of the primary tumor cells in the nearby tissues. As the malignant cells continue to proliferate and the tumor increases in size, the cells undergo continuous mutation and alteration increasing its metastatic potential. This phrase will start as the individualize tumor cell escapes the primary tumor. Detachment occurs as the tumor cells undergo Epithelial-mesenchymal Transition (EMT) leading to alteration in the cell-to-cell and cell-to-matrix adhesion and degradation of the extracellular matrix enabling penetration of the tumor cells to the surrounding tissue boundaries. EMT induction results to decrease receptor response to E-cadherin and activation of mesenchymal markers like N-cadherin. Cadherins are transmembrane proteins which act as cell adhesion molecules that bind cell to cell junctions. In breast carcinoma, E-Cadherin gene mutates leading to a reduced or abolished protein function and diminish extracellular matrix integrity. The bond between breast epithelial cells and the epithelial cancer cells diminishes along with the levels of E-Cadherin. On the other hand, N-Cadherin allows the connection between tumor and stromal cells permitting cancer cell invasion and infiltration of the adjacent tissue. During stroma invasion, most epithelial cancer cells showed an increasing proportion of N-Cadherin and a decreased proportion of E-Cadherin. The cancer cells also produce proteins which can degrade basement membrane allowing the malignant cells to break the bond that tether them to the tumor. The release of proteases–extracellular matrix-degrading enzymes further erode the basement membrane resulting to the cut in the barrier where the malignant cells pass through and escape. The cells undergo changes resulting in an elongated fibroblast-like shape which can further facilitate movements across membrane channels.
Once the malignant cells penetrate the basement membrane, it can have access to the complex networks of the lymphatic system and circulatory vessels. It can infiltrate lymphatic vessel or blood vessel walls and spread via the bloodstream to other parts of the body and secondary sites for metastasis. This process is known as the intravasation. In lymphatic intravasation, the tumor cells enter the lymphatic vessels, traverse into the series of lymph nodes then capillaries and have access to the bloodstream as lymph drains back to the venous circulation. Some cancer cells can get trapped in the lymph node. Hence, sentinel lymph nodes, those closest to the primary tumor are often the first sites of metastasis. The tumor cells can also generate growth of the vascular network through angiogenesis. In angiogenesis, new blood and lymphatic vessels are formed, providing increase blood nutrients supply vital for cancer growth and additional pathway where cancer epithelial cells escape.
After intravasation, tumor cells can be detected as circulating tumor cells in either the blood of lymphatic circulation. The circulating tumor cells can migrate singly or collectively. During transit, some tumor cells may break down as it moves and bumps to the walls of the veins and arteries while some erode as it enters narrow pathways. The immune response is also triggered causing the immune system to attack the site and halt the progression of metastasis. Some malignant cells may die in the process while other can lay dormant for years. If the circulating tumor cells survive, it disseminates via the bloodstream, lodge on the wall of the blood vessels and then adheres to the capillary bed of the next target organ. Over time, the malignant cells will move to pass thru the blood vessel wall and start to infiltrate the tissues. The cancer cells will now start to settle and develop into a new tumor in the organ where it migrated. The malignant cells then repeat the process and can proceed to infiltrate the new host tissue completing the phases of the secondary metastasis.
Any type of breast cancer can metastasize. It is important to note that a metastatic cancer cell is not identified by the body part where it migrated but by the primary tumor. This means that a breast cancer that metastasized to the lungs is not a lung cancer but a breast cancer cell. As metastatic breast cancer remains to be the primary cause of death among breast cancer patients, detection of the breast cancer metastasis at the earliest stage is an important indicator of breast cancer progression prediction and breast cancer treatment success.