Archived Comments for:
Aldehyde dehydrogenase and estrogen receptor define a hierarchy of cellular differentiation in the normal human mammary epithelium
Plasticity of ER expression of Mammary Stem Cells which may harbor Anti-redox Machinery
Go Yoshida, Tokyo Medical and Dental University
18 December 2014
Honeth G, et al have recently elucidated the hierarchy model of mammary tissue and breast cancer from the novel perspective of the interaction between estrogen receptor (ER) and aldehyde dehydrogenase1 (ALDH1) [1]. I would like to deepen the consideration on the ‘stemness’ in EpCAM-negative/lin-negative/CD49f-positive mammary cells. Stemness includes several phenotypes characterized by self-renewal potential, multi-lineage differentiation, and plasticity between stem cells and transit-amplifying cells (TA cells).
Firstly, Figure1 in [1] indicates the inversed correlation between ER and ALDHA1/A3 in human mammary epithelial cells, which is also supported by the previous report that ER-positive breast cancer cells express much less amount of CD44 variant 7-10 (CD44v isoform in which variable exons 7-10 are inserted) than ER-negative cells [2]. In contrast, some researchers claim that CD44v8-10 is positively correlated with EGFR expression, whereas CD44 standard isoform (CD44s) in basal cells is positively correlated with HER2, one of the transmembrane tyrosine kinase receptors [3]. CD44v is widely recognized as one of the cancer stem cell markers, and induced by the alternative splicing machinery depending on the epithelial splicing regulatory protein (ESRP) [4]. In particular, ESRP1-CD44v-xCT-glutathione (GSH) axis promotes circulating breast cancer cells to survive and proliferate in the pre-metastatic niche [5]. Thus, it is likely that not only ALDHA1/A3 isoforms but also CD44v can be a useful marker to identify normal mammary stem cells and a functional stem cell marker for anti-redox stress via CD44v-xCT-GSH axis in the morphogenesis or spheroid formation.
Secondly, Figure2 and 3 in [1] show that ER-negative mammary cells are relatively undifferentiated and produce TA cells which are positive for ER. In particular, Figure3S demonstrates that ER-positive cells cannot form spheroids in three-dimensional (3D) culture regardless of their higher proliferative ability. However, IHC analysis of xenograft models derived from ER-positive or-negative human cells reveals in Figure3J-Q that there is heterogeneity of ER expression in epithelial ducts. Given that ER-negative cells give rise to ER-positive precursor cells, there may exists plasticity between stem cells and TA cells in terms of ER expression. Indeed, this plasticity prevents the exhaustion of the mammary stem cell pool, and further, the gradient of retinoic acid (RA) and the difference in the susceptibility to this ligand depending on the expression level of its nuclear receptor ER are expected to play a pivotal role in morphogenesis, wound healing, and the prevention of the clonal expansion of malignant transformed cells.
References
1. Honeth G, Lombardi S, Ginestier C, Hur M, Marlow R, Buchupalli B, Shinomiya I, Gazinska P, Bombelli S, Ramalingam V et al: Aldehyde dehydrogenase and estrogen receptor define a hierarchy of cellular differentiation in the normal human mammary epithelium. Breast cancer research : BCR 2014, 16(3):R52.
2. Hole AK, Belkhiri A, Snell LS, Watson PH: CD44 variant expression and estrogen receptor status in breast cancer. Breast cancer research and treatment 1997, 43(2):165-173.
3. Olsson E, Honeth G, Bendahl PO, Saal LH, Gruvberger-Saal S, Ringner M, Vallon-Christersson J, Jonsson G, Holm K, Lovgren K et al: CD44 isoforms are heterogeneously expressed in breast cancer and correlate with tumor subtypes and cancer stem cell markers. BMC cancer 2011, 11:418.
4. Yoshida GJ, Saya H: Inversed relationship between CD44 variant and c-Myc due to oxidative stress-induced canonical Wnt activation. Biochemical and biophysical research communications 2014, 443(2):622-627.
5. Yae T, Tsuchihashi K, Ishimoto T, Motohara T, Yoshikawa M, Yoshida GJ, Wada T, Masuko T, Mogushi K, Tanaka H et al: Alternative splicing of CD44 mRNA by ESRP1 enhances lung colonization of metastatic cancer cell. Nature communications 2012, 3:883.
Plasticity of ER expression of Mammary Stem Cells which may harbor Anti-redox Machinery
Go Yoshida, School of Medicine, Keio University
12 January 2015
This research has elucidated the hierarchy model of mammary tissue and breast cancer from the novel perspective of the interaction between ER and ALDH. I would like to write the comment on the “stemness,” (including self-renewal potential, multi-lineaged differentiation and plasticity) in EpCAM-negative/lin-negative/CD49f-positive mammary cells.
Firstly, Figure1 indicates the inversed correlation between estrogen receptor (ER) and ALDHA1/A3 in human mammary epithelial cells, which is also supported by the previous report that ER-positive breast cancer cells express much less amount of CD44 variant 7-10 (CD44v isoform in which variable exons 7-10 are inserted) than ER-negative cells (Breast Cancer Res Treat.1997;43:165-73.). In contrast, some researchers claim that CD44v8-10 is positively correlated with EGFR expression, whereas CD44 standard isoform in basal cells is positively correlated with HER2 (BMC Cancer 2011;11:418.). CD44v is widely recognized as one of the cancer stem cell markers, and induced by the alternative splicing machinery depending on epithelial splicing regulatory protein (ESRP)1. ESRP1-CD44v-xCT-glutathione (GSH) axis promotes circulating breast cancer cells to survive and proliferate in the pre-metastatic niche (Nat Commun. 2012;3:883.). Thus, does it strongly suggests that not only ALDHA1/A3 isoforms but also CD44v can be a useful marker to identify normal mammary stem cells and functional for anti-redox stress via CD44v-xCT-GSH axis in the morphogenesis or spheroid formation?
Secondly, Figure2 and 3 show that ER-negative mammary cells are relatively undifferentiated and produce transit-amplifying cells (TA cells) which are positive for ER. In particular, Figure3S demonstrates that ER-positive cells cannot form spheroids in 3D culture regardless of their higher proliferative ability. However, IHC analysis of xenograft models derived from ER-positive or-negative human cells reveals in Figure3J-Q that there is heterogeneity of ER expression in epithelial ducts. Given that ER-negative cells give rise to ER-positive precursor cells, is there any plasticity between stem cells and TA cells in terms of ER expression?
Plasticity of ER expression of Mammary Stem Cells which may harbor Anti-redox Machinery
18 December 2014
Honeth G, et al have recently elucidated the hierarchy model of mammary tissue and breast cancer from the novel perspective of the interaction between estrogen receptor (ER) and aldehyde dehydrogenase1 (ALDH1) [1]. I would like to deepen the consideration on the ‘stemness’ in EpCAM-negative/lin-negative/CD49f-positive mammary cells. Stemness includes several phenotypes characterized by self-renewal potential, multi-lineage differentiation, and plasticity between stem cells and transit-amplifying cells (TA cells).
Firstly, Figure1 in [1] indicates the inversed correlation between ER and ALDHA1/A3 in human mammary epithelial cells, which is also supported by the previous report that ER-positive breast cancer cells express much less amount of CD44 variant 7-10 (CD44v isoform in which variable exons 7-10 are inserted) than ER-negative cells [2]. In contrast, some researchers claim that CD44v8-10 is positively correlated with EGFR expression, whereas CD44 standard isoform (CD44s) in basal cells is positively correlated with HER2, one of the transmembrane tyrosine kinase receptors [3]. CD44v is widely recognized as one of the cancer stem cell markers, and induced by the alternative splicing machinery depending on the epithelial splicing regulatory protein (ESRP) [4]. In particular, ESRP1-CD44v-xCT-glutathione (GSH) axis promotes circulating breast cancer cells to survive and proliferate in the pre-metastatic niche [5]. Thus, it is likely that not only ALDHA1/A3 isoforms but also CD44v can be a useful marker to identify normal mammary stem cells and a functional stem cell marker for anti-redox stress via CD44v-xCT-GSH axis in the morphogenesis or spheroid formation.
Secondly, Figure2 and 3 in [1] show that ER-negative mammary cells are relatively undifferentiated and produce TA cells which are positive for ER. In particular, Figure3S demonstrates that ER-positive cells cannot form spheroids in three-dimensional (3D) culture regardless of their higher proliferative ability. However, IHC analysis of xenograft models derived from ER-positive or-negative human cells reveals in Figure3J-Q that there is heterogeneity of ER expression in epithelial ducts. Given that ER-negative cells give rise to ER-positive precursor cells, there may exists plasticity between stem cells and TA cells in terms of ER expression. Indeed, this plasticity prevents the exhaustion of the mammary stem cell pool, and further, the gradient of retinoic acid (RA) and the difference in the susceptibility to this ligand depending on the expression level of its nuclear receptor ER are expected to play a pivotal role in morphogenesis, wound healing, and the prevention of the clonal expansion of malignant transformed cells.
References
1. Honeth G, Lombardi S, Ginestier C, Hur M, Marlow R, Buchupalli B, Shinomiya I, Gazinska P, Bombelli S, Ramalingam V et al: Aldehyde dehydrogenase and estrogen receptor define a hierarchy of cellular differentiation in the normal human mammary epithelium. Breast cancer research : BCR 2014, 16(3):R52.
2. Hole AK, Belkhiri A, Snell LS, Watson PH: CD44 variant expression and estrogen receptor status in breast cancer. Breast cancer research and treatment 1997, 43(2):165-173.
3. Olsson E, Honeth G, Bendahl PO, Saal LH, Gruvberger-Saal S, Ringner M, Vallon-Christersson J, Jonsson G, Holm K, Lovgren K et al: CD44 isoforms are heterogeneously expressed in breast cancer and correlate with tumor subtypes and cancer stem cell markers. BMC cancer 2011, 11:418.
4. Yoshida GJ, Saya H: Inversed relationship between CD44 variant and c-Myc due to oxidative stress-induced canonical Wnt activation. Biochemical and biophysical research communications 2014, 443(2):622-627.
5. Yae T, Tsuchihashi K, Ishimoto T, Motohara T, Yoshikawa M, Yoshida GJ, Wada T, Masuko T, Mogushi K, Tanaka H et al: Alternative splicing of CD44 mRNA by ESRP1 enhances lung colonization of metastatic cancer cell. Nature communications 2012, 3:883.
Abbreviations
ALDH: Aldehyde dehydrogenase, CD44s: CD44 standard isoform, CD44v: CD44 variant isoform, EGFR: Epidermal growth factor receptor, EpCAM: Epithelial cell adhesion molecule, ER: Estrogen receptor, ESRP: Epithelial splicing regulatory protein, GSH: Glutathione, IHC: immunohistochemistry, RA: retinoic acid, TA cells: transit amplifying cells, 3D: three-dimensional
Competing interests
The author declares no competing interests.
Plasticity of ER expression of Mammary Stem Cells which may harbor Anti-redox Machinery
12 January 2015
This research has elucidated the hierarchy model of mammary tissue and breast cancer from the novel perspective of the interaction between ER and ALDH. I would like to write the comment on the “stemness,” (including self-renewal potential, multi-lineaged differentiation and plasticity) in EpCAM-negative/lin-negative/CD49f-positive mammary cells.
Firstly, Figure1 indicates the inversed correlation between estrogen receptor (ER) and ALDHA1/A3 in human mammary epithelial cells, which is also supported by the previous report that ER-positive breast cancer cells express much less amount of CD44 variant 7-10 (CD44v isoform in which variable exons 7-10 are inserted) than ER-negative cells (Breast Cancer Res Treat.1997;43:165-73.). In contrast, some researchers claim that CD44v8-10 is positively correlated with EGFR expression, whereas CD44 standard isoform in basal cells is positively correlated with HER2 (BMC Cancer 2011;11:418.). CD44v is widely recognized as one of the cancer stem cell markers, and induced by the alternative splicing machinery depending on epithelial splicing regulatory protein (ESRP)1. ESRP1-CD44v-xCT-glutathione (GSH) axis promotes circulating breast cancer cells to survive and proliferate in the pre-metastatic niche (Nat Commun. 2012;3:883.). Thus, does it strongly suggests that not only ALDHA1/A3 isoforms but also CD44v can be a useful marker to identify normal mammary stem cells and functional for anti-redox stress via CD44v-xCT-GSH axis in the morphogenesis or spheroid formation?
Secondly, Figure2 and 3 show that ER-negative mammary cells are relatively undifferentiated and produce transit-amplifying cells (TA cells) which are positive for ER. In particular, Figure3S demonstrates that ER-positive cells cannot form spheroids in 3D culture regardless of their higher proliferative ability. However, IHC analysis of xenograft models derived from ER-positive or-negative human cells reveals in Figure3J-Q that there is heterogeneity of ER expression in epithelial ducts. Given that ER-negative cells give rise to ER-positive precursor cells, is there any plasticity between stem cells and TA cells in terms of ER expression?
Competing interests
No Competing Interests Exist.