Metaplastic Breast Cancer
Breast cancer that is metaplastic (MpBC) is an extremely rare type of breast cancer that is both therapeutically difficult and highly aggressive. MpBC is recognized by the histological presence of at minimum two cellular types, usually epithelial or mesenchymal types. The variant is characterized by an atypical tri-negative cancer (TNBC) but is associated with a lower prognosis and less survival when compared to TNBC. There is currently no standard treatments for MpBC.
However, prior studies have found that MpBC typically has molecular alterations in epithelial-to-mesenchymal transition, amplification of epidermal growth factor receptor, PI3K/Akt signaling, nitric oxide signaling, Wnt/b-catenin signaling, altered immune response, and cell cycle dysregulation. A few of these changes are being studied as potential therapeutic targets at both the preclinical as well as clinical context. The current review examines the histological and the cellular roots of MpBC molecular changes and the function of radiation therapy and the current clinical trials being conducted for MpBC.
Histological arrangement of MpBC
Metaplastic carcinomas are composed of several cell populations that have undergone metaplastic differentiation meaning that cells have transformed into non-glandular glandular form 6[ 6 ]. Metaplastic changes can be described as cancerous (squamous) as well as sarcomatous components that include chondroid, osseous and spindle morphology 11. It is the WHO Classification of Breast Tumors categorizes MpBC as a mixed metaplastic carcinoma, low-grade adenosquamous cancer and fibromatosis-like squamous cell tumor and spindle cell carcinoma and metaplastic carcinoma that has mesenchymal differentiation 1, 77. Each of these metaplastic forms are chemoresistant and aggressive, and are highly likely to develop metastasis, with the exception of fibromatosis like cancer and low-grade adenosquamous carcinoma
Understanding the distinctions between histological types could give insight into the clinical prognosis and therapeutic possibilities. For instance, Schwartz and colleagues organized MpBC into epithelial and mixed types with epithelial forms including the squamous-cell carcinoma, adenocarcinoma exhibiting spindle cell differentiation, as well as Adenosquamous cancer, while mixed types comprised carcinomas with chondroid metaplasia and carcinoma with osseous metaplasia, as well as carcinosarcoma 99.
Tse as well as colleagues identified MpBC into three types epithelial-only cancer, biphasic epithelial and Sarcomatoid cancer, and monophasic spindle cell carcinoma 1010. Oberman conducted a clinical pathological study of 29 patients who had primary breast cancers that identified MpBC in three categories: spindle cell cancer as well as invasive ductal cancer with large squamous metaplasia, as well as an invasive ductal carcinoma that has metaplasia pseudosarcomatous 1111. One of the main difficulties with these classifications is that there is no relationship between the microscopic patterns and the prognosis for the disease partly because of the rare nature in the biology of this disease.
One of these from Song et al. discovered that there was a clinical significance in sub-classifying MpBC as a sub-type of MpBC 1212. The study revealed that the prognosis for MpBC was more dire than the triple-negative invasive tumor (TN-IDC) and had 5-year survival rates of 54.5 percent against. 73.3 percentage in both cases. Adenocarcinoma which has spindle cell division had the lowest five-year survival rate, which was 40 percent. The study in all its entirety concluded that the distinction of MpBC by histological variations might be of clinical significance.
Cell source of MpBC
The clonality and the origins of MpBC has been debated for many years There exist at least three possible explanations to explain the reasons MpBC are biphasic tumors which means that they have cancerous and sarcomatous parts in the same cancer. A collision model suggests the carcinomatous and sarcomatous tissue originate from progenitors that are distinct 9While the multiclonal theory indicates that the same progenitor cell is responsible the development of both carcinomatous and sarcomatous cells. The conversion/metaplastic theory suggests that the sarcomatous components derive from the carcinomatous component via a metaplastic process. Evidence for the metaplastic hypothesis comes from studies that show both mesenchymal and epithelial components of the tumor exhibit an increase in S-100, cytokeratin, and vimentin 1818. Additionally, it has been thought that MpBC could originate from myoepithelial cells as the tumors are often positivity for the myoepithelial marker such as CD10, p63 and smooth muscle actin
Epithelial-to-mesenchymal transition
Epithelial-to-mesenchymal transition (EMT) is a transient process in which epithelial cells lose their cell polarity and cell-cell adhesion qualities and acquire mesenchymal properties, including enhanced migratory capacity, resistance to apoptosis and chemotherapy, invasiveness, and characteristic morphological and gene expression changes EMT that occurs after embryogenesis is regarded as an illness, and the process is associated with the loss of claudin and E-cadherin expression, as well as increased mesenchymal markers, like vimentin as well as Smooth muscle cell actin 3939.
EMT is typically controlled via transcription factors (TF) like Goosecoid, Snail, Slug Twist FOXC1, FOXC2, Zeb1 and Zeb2 ZEB2 and Zeb1 2020. While EMT is extensively researched in metaplastic and claudin-low breast cancers EMT is also involved in the development of various cancers like prostate, lung, liver thyroid, pancreas and glioblastoma multiforme 40, 41[ 40, 41]. In general the tumors which undergo EMT usually exhibit epithelial characteristics and activated EMT-TF-dependent cell processes, including dedifferentiation, and the ability to change 41.
Taube and coworkers conducted research in which they discovered an EMT fundamental DNA signature enhanced for genes controlled by Zeb1 and this signature was in line with the metaplastic and claudin-low breast cancers 2020. Hennessy et al. discovered similar results from their study where the 28 MpBC specimens of tumor were transiently measured and probed with an initial tumor cell (TIC) gene signature 2121. The TIC Gene Signature was created in the lab of Creighton et al. .
MpBC tumors had a similar genetic signature with TIC and Claudin-low breast cancer genes and had more stem-cell-like characteristics and expressed significant amounts of EMT markers]. TICs are observed more frequently during chemotherapy or endocrine therapy they are also resistant to chemotherapy, show EMT characteristics that allow for self-renewal 2222. One of the most important findings from this research was the fact that MpBC had a higher frequency of amplification, mutation and activation of the phosphoinositide 3-kinase (PI3K) signaling compared to claudin-low and basal breast cancers. So, the presence of EMT/stem cells combined with PI3K signaling hyperactivation could explain why MpBC is a highly unresponsive, chemorefractory type and could be derived from an eukaryotic stem cell.
Epidermal growth factor receptor (EGFR)
MpBC frequently increases the expression of EGFR however, it is not atypically deficient in HER2 amplification and overexpression 2323. Reis-Filho and coworkers found that 34 percent of MpBC patients exhibit EGFR gene amplification. This gene amplification is linked to the overexpression of genes 2424. The study did not find active mutations found in EGFR which suggests that point mutations in the receptor will not affect the overexpression of EGFR. Another study looked at the 77 MpBC samples and discovered that the majority of the samples tested positive for the p63 gene (59 percent) and cytokeratin 5/6 (58 percent), EGFR overexpression (66 percent) and KIT (24 percent) 24%) 2525.
The study also revealed no mutations that activated EGFR or KIT. The fluorescence in situ hybridization used to demonstrate a the high EGFR copy number due to aneusomy (22 percentage) and amplifying (4 4 percent). To examine the different patterns in the EGFR Amplification between MpBC and mesenchymal as well as basal TNBC tumours, the researchers carried out the analysis of droplet digital PCR (ddPCR) to evaluate the EGFR DNA copy numbers. We utilized DNA extracted from established MpBC as well as TNBC patient-derived , xenograft (PDX) TNBC tumors.
The specifics of the study are described in the additional information. We discovered that in contrast the mesenchymal TNBC and MpBC TNBC, base TNBC was the most abundant in EGF copy numbers. PDX BCM-4013 (basal-like 2 subtype, B2) showed the highest EGFR Amplification of all PDXs. The BL2 TNBC tumors were found to have increased EGFR gene expression 4242. 50 percent of MpBC PDX tumors showed the EGFR copies with a copy number greater than two. These findings provide insight into the different manifestation of EGFR between TNBC and MpBC and also require further research into the use of EGFR inhibitors of tyrosine kinase as treatment options against MpBC.
metaplastic breast cancer
Breast cancer that is metaplastic (MpBC) is an extremely rare type of breast cancer that is both therapeutically difficult and highly aggressive.
MpBC is recognized by the histological presence of at minimum two cellular types, usually epithelial or mesenchymal types. The variant is characterized by an atypical tri-negative cancer (TNBC) but is associated with a lower prognosis and less survival when compared to TNBC.
There is currently no standard treatments for MpBC. However, prior studies have found that MpBC typically has molecular alterations in epithelial-to-mesenchymal transition, amplification of epidermal growth factor receptor, PI3K/Akt signaling, nitric oxide signaling, Wnt/b-catenin signaling, altered immune response, and cell cycle dysregulation.
A few of these changes are being studied as potential therapeutic targets at both the preclinical as well as clinical context. The current review examines the histological and the cellular roots of MpBC molecular changes and the function of radiation therapy and the current clinical trials being conducted for MpBC.
Histological arrangement of MpBC
Metaplastic carcinomas are composed of several cell populations that have undergone metaplastic differentiation meaning that cells have transformed into non-glandular glandular form 6[ 6 ]. Metaplastic changes can be described as cancerous (squamous) as well as sarcomatous components that include chondroid, osseous and spindle morphology 11.
It is the WHO Classification of Breast Tumors that categorizes MpBC as a mixed metaplastic carcinoma, low-grade adenosquamous cancer and fibromatosis-like squamous cell tumor and spindle cell carcinoma and metaplastic carcinoma that has mesenchymal differentiation 1, 77. Each of these metaplastic forms is chemoresistant and aggressive, and are highly likely to develop metastasis, with the exception of fibromatoses like cancer and low-grade adenosquamous carcinoma
Understanding the distinctions between histological types could give insight into the clinical prognosis and therapeutic possibilities. For instance, Schwartz and colleagues organized MpBC into epithelial and mixed types with epithelial forms including the squamous-cell carcinoma, adenocarcinoma exhibiting spindle cell differentiation, as well as Adenosquamous cancer, while mixed types comprised carcinomas with chondroid metaplasia and carcinoma with osseous metaplasia, as well as carcinosarcoma 99.
Tse as well as colleagues identified MpBC into three types epithelial-only cancer, biphasic epithelial and Sarcomatoid cancer, and monophasic spindle cell carcinoma 1010. Oberman conducted a clinical pathological study of 29 patients who had primary breast cancers that identified MpBC in three categories: spindle cell cancer as well as invasive ductal cancer with large squamous metaplasia, as well as an invasive ductal carcinoma that has metaplasia pseudosarcomatous 1111.
One of the main difficulties with these classifications is that there is no relationship between the microscopic patterns and the prognosis for the disease partly because of the rare nature in the biology of this disease.
One of these from Song et al. discovered that there was a clinical significance in sub-classifying MpBC as a sub-type of MpBC 1212. The study revealed that the prognosis for MpBC was more dire than the triple-negative invasive tumor (TN-IDC) and had 5-year survival rates of 54.5 percent against. 73.3 percentage in both cases. Adenocarcinoma which has spindle cell division had the lowest five-year survival rate, which was 40 percent. The study in all its entirety concluded that the distinction of MpBC by histological variations might be of clinical significance.
Cell source of MpBC
The clonality and the origins of MpBC has been debated for many years There exist at least three possible explanations to explain the reasons MpBC are biphasic tumors which means that they have cancerous and sarcomatous parts in the same cancer. A collision model suggests the carcinomatous and sarcomatous tissue originate from progenitors that are distinct 9While the multiclonal theory indicates that the same progenitor cell is responsible the development of both carcinomatous and sarcomatous cells.
The conversion/metaplastic theory suggests that the sarcomatous components derive from the carcinomatous component via a metaplastic process. Evidence for the metaplastic hypothesis comes from studies that show both mesenchymal and epithelial components of the tumor exhibit an increase in S-100, cytokeratin, and vimentin 1818. Additionally, it has been thought that MpBC could originate from myoepithelial cells as the tumors are often positivity for the myoepithelial marker such as CD10, p63 and smooth muscle actin
Epithelial-to-mesenchymal transition
Epithelial-to-mesenchymal transition (EMT) is a transient process in which epithelial cells lose their cell polarity and cell-cell adhesion qualities and acquire mesenchymal properties, including enhanced migratory capacity, resistance to apoptosis and chemotherapy, invasiveness, and characteristic morphological and gene expression changes EMT that occurs after embryogenesis is regarded as an illness, and the process is associated with the loss of claudin and E-cadherin expression, as well as increased mesenchymal markers, like vimentin as well as Smooth muscle cell actin 3939.
EMT is typically controlled via transcription factors (TF) like Goosecoid, Snail, Slug Twist FOXC1, FOXC2, Zeb1 and Zeb2 ZEB2 and Zeb1 2020. While EMT is extensively researched in metaplastic and claudin-low breast cancers EMT is also involved in the development of various cancers like prostate, lung, liver thyroid, pancreas and glioblastoma multiforme 40, 41[ 40, 41]. In general the tumors which undergo EMT usually exhibit epithelial characteristics and activated EMT-TF-dependent cell processes, including dedifferentiation, and the ability to change 41
Taube and coworkers conducted research in which they discovered an EMT fundamental DNA signature enhanced for genes controlled by Zeb1 and this signature was in line with the metaplastic and claudin-low breast cancers 2020. Hennessy et al. discovered similar results from their study where the 28 MpBC specimens of tumor were transiently measured and probed with an initial tumor cell (TIC) gene signature 2121.
The TIC Gene Signature was created in the lab of Creighton et al. . MpBC tumors had a similar genetic signature with TIC and Claudin-low breast cancer genes and had more stem-cell-like characteristics and expressed significant amounts of EMT markers]. TICs are observed more frequently during chemotherapy or endocrine therapy they are also resistant to chemotherapy, show EMT characteristics that allow for self-renewal 2222.
One of the most important findings from this research was the fact that MpBC had a higher frequency of amplification, mutation and activation of the phosphoinositide 3-kinase (PI3K) signaling compared to claudin-low and basal breast cancers. So, the presence of EMT/stem cells combined with PI3K signaling hyperactivation could explain why MpBC is a highly unresponsive, chemorefractory type and could be derived from an eukaryotic stem cell.
Epidermal growth factor receptor (EGFR)
MpBC frequently increases the expression of EGFR however, it is not atypically deficient in HER2 amplification and overexpression 2323. Reis-Filho and coworkers found that 34 percent of MpBC patients exhibit EGFR gene amplification. This gene amplification is linked to the overexpression of genes 2424. The study did not find active mutations found in EGFR which suggests that point mutations in the receptor will not affect the overexpression of EGFR.
Another study looked at the 77 MpBC samples and discovered that the majority of the samples tested positive for the p63 gene (59 percent) and cytokeratin 5/6 (58 percent), EGFR overexpression (66 percent) and KIT (24 percent) 24%) 2525. The study also revealed no mutations that activated EGFR or KIT. The fluorescence in situ hybridization used to demonstrate a the high the EGFR copy number due to aneusomy (22 percentage) and amplifying (4 4 percent).
To examine the different patterns in the EGFR Amplification between MpBC and mesenchymal as well as basal TNBC tumours, the researchers carried out the analysis of droplet digital PCR (ddPCR) to evaluate the EGFR DNA copy numbers. We utilized DNA extracted from established MpBC as well as TNBC patient-derived, xenograft (PDX) TNBC tumors. The specifics of the study are described in the additional information. We discovered that in contrast the mesenchymal TNBC and MpBC TNBC, base TNBC was the most abundant in EGF copy numbers. PDX BCM-4013 (basal-like 2 subtype, B2) showed the highest EGFR Amplification of all PDXs.
The BL2 TNBC tumors were found to have increased EGFR gene expression 4242. 50 percent of MpBC PDX tumors showed the EGFR copies with a copy number greater than two. These findings provide insight into the different manifestation of EGFR between TNBC and MpBC and also require further research into the use of EGFR inhibitors of tyrosine kinase as treatment options against MpBC.
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