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It is no news that breast cancer is the most common cancer among women and the highest cause of cancer-related deaths among women worldwide. According to WHO, in 2020, 2.3 million women were diagnosed with breast cancer with 685,000 reported mortality. Arguably, the worst news that can be given to a breast cancer survivor is of recurrence -“the cancer is back”. Sadly, with the advances in cancer research, local or metastatic recurrence remains a thorn in the side of cancer researchers, oncologists and patients. It is, therefore, crucial to have a better understanding of the factors that are responsible for a breast cancer relapse, to give breast cancer patients a better chance of recurrence-free survival. Breast cancer recurrence varies from one patient to another and it depends on the subtype of breast cancer and a variety of other factors. In some cases, breast cancers can recur after 3 to 5 years of initial treatment while in other cases, it may take a longer time.
There are 5 main subtypes of breast cancer based on the presence of hormone receptors for estrogen (ER), progesterone (PR) and human epidermal growth factor 2 (HER2). They are luminal A, luminal B, triple-negative, HER2-enriched and normal-like subtypes, all of which differ in terms of occurrence, recurrence and prognosis. For example, the luminal A subtype was found to be more commonly diagnosed and have the best prognosis while the triple-negative subtype was found to have the worst prognosis.
About 75% of all breast cancers are ER-positive and, studies and clinical outcomes have revealed that, in many cases, ER-positive breast cancers tend to recur later in life than ER-negative breast cancers. Hence, it is important to understand the mechanism of action responsible for the late recurrence of these groups of breast cancer to improve the chances of overall complete survival.
The late recurrence of ER-positive breast cancers has been reported to be attributed to the reactivation of dormant disseminated tumor cells (cancer cells that have left the primary tumor to survive in the circulation), which, upon reactivation and under appropriate conditions, can cause metastatic recurrence, the main cause of cancer death. For instance, researchers in Japan reported a case of an elderly woman with adenocarcinoma in the left lungs after 23 years of successful treatment of ER-positive breast cancer. The morphological features and immunohistochemical staining of the adenocarcinoma cells in the left lungs confirmed it to be a metastatic relapse from the initial breast cancer. The study further reported that the reawakening of dormant disseminated ER-positive breast cancer cells is responsible for the late recurrence.
Furthermore, studies reported that some ER-positive breast cancer cells were found to express more dormancy-related genes compared to ER-negative cells, suggesting the ability of disseminated tumor cells of ER-positive breast cancer cells to survive in a state of dormancy for a longer time, hence the late recurrence. Therefore, it would be beneficial to identify proteins that are responsible for regulating dormancy in this type of breast cancer to mitigate the process of recurrence. One of the proteins that have been linked to tumor dormancy in bone disseminated breast cancer is Mitogen and Stress Activated Protein Kinase 1 (MSK1).
MSK1 is a serine/threonine protein kinase, found predominantly in the nucleus. It is activated by ERK1/2 and p38/MAPK pathways in response to mitogens/growth factors and stress respectively (Fig 1). MSK1 can be regulated at multiple phosphorylation sites in cells and its activation can be inhibited by suppressing the ERK and p38 pathways.
In ER-positive breast cancer, low levels of MSK1 is associated with early induction of metastasis while expression of MSK1 is associated with late metastasis. A gene knockdown study performed by researchers in Spain, using ER-positive breast cancer cells revealed that the knockdown of the MSK1 gene promotes bone metastasis of luminal breast cancer cells. Loss of MSK1 was found to alter chromatin structure, resulting in reduced expression of luminal differentiation genes, thereby promoting bone metastasis. The study suggests that MSK1 might have a significant role in the late relapse of ER-positive breast cancer patients.
To further elucidate the roles of MSK1 in dormant ER-positive breast cancers and translate the study to clinical use, suitable and clinically relevant models are required. In tumor dormancy research, one of the major limitations to clinical trials is the unavailability of suitable models to accurately depict the mode of action of dormant tumor cells in humans. Studies have been done using 2D and 3D culture models, in vivo mouse models, human tumor xenografts and bioengineered models using tissue engineering techniques, all of which has been beneficial in tumor dormancy research. However, due to the complexity of dormant tumor cells, the available models have various limitations that prevent the translation of tumor dormancy research to clinical use. So, research into more clinically suitable models would be required to effectively study dormancy in ER+ breast cancer and increase recurrence-free survival among breast cancer patients.
Edited by: Manisit Das
Header image: https://www.flickr.com/photos/30478819@N08/44407488405
Bushnell, G., Deshmukh, A.,Hollander, P et al (2021). Breast cancer dormancy: need for clinically relevant models to address current gaps in knowledge. npj Breast Cancer 7:66
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Gawrzak, S., Rinaldi, L., Gregorio, S. et al (2018). MSK1 regulates luminal cell differentiation and metastatic dormancy in ER+ breast cancer. Nature Cell Biology 20: 211-221
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