Solid tumours are an enormous cancer burden and a major therapeutic challenge. The cancer stem cell (CSC) hypothesis provides an attractive cellular mechanism to account for the therapeutic refractoriness and dormant behaviour exhibited by many of these tumours. There is increasing evidence that diverse solid tumours are hierarchically organized and sustained by a distinct subpopulation of CSCs. Direct evidence for the CSC hypothesis has recently emerged from mouse models of epithelial tumorigenesis, although alternative models of heterogeneity also seem to apply. The clinical relevance of CSCs remains a fundamental issue but preliminary findings indicate that specific targeting may be possible.

Cancer stem cells in solid tumours: accumulating evidence and unresolved questions

Tumors are cellularly and molecularly heterogeneous, with subsets of undifferentiated cancer cells exhibiting stem cell-like features (CSCs). Epithelial to mesenchymal transitions (EMT) are transdifferentiation programs that are required for tissue morphogenesis during embryonic development. The EMT process can be regulated by a diverse array of cytokines and growth factors, such as transforming growth factor (TGF)-β, whose activities are dysregulated during malignant tumor progression. Thus, EMT induction in cancer cells results in the acquisition of invasive and metastatic properties. Recent reports indicate that the emergence of CSCs occurs in part as a result of EMT, for example, through cues from tumor stromal components. Recent evidence now indicates that EMT of tumor cells not only causes increased metastasis, but also contributes to drug resistance. In this review, we will provide potential mechanistic explanations for the association between EMT induction and the emergence of CSCs. We will also highlight recent studies implicating the function of TGF-β-regulated noncoding RNAs in driving EMT and promoting CSC self-renewal. Finally we will discuss how EMT and CSCs may contribute to drug resistance, as well as therapeutic strategies to overcome this clinically.

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EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer

Stem cells are defined as cells able to both extensively self-renew and differentiate into progenitors. Research data show that more resistant stem cells than common cancer cells exist in cancer patients.To identify unrecognized differences between cancer stem cells and cancer cells might be able to develope effective classification,diagnose and treat ment for cancer.

Stem Cells,Cancer and Cancer Stem Cells

Introduction
In breast cancer, gene expression analyses have defined five tumor subtypes (luminal A, luminal B, HER2-enriched, basal-like and claudin-low), each of which has unique biologic and prognostic features. Here, we comprehensively characterize the recently identified claudin-low tumor subtype.

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Phenotypic and molecular characterization of the claudin-low intrinsic subtype of breast cancer

Basal-like breast cancers arising in women carrying mutations in the BRCA1 gene, encoding the tumor suppressor protein BRCA1, are thought to develop from the mammary stem cell. To explore early cellular changes that occur in BRCA1 mutation carriers, we have prospectively isolated distinct epithelial subpopulations from normal mammary tissue and preneoplastic specimens from individuals heterozygous for a BRCA1 mutation. We describe three epithelial subsets including basal stem/progenitor, luminal progenitor and mature luminal cells. Unexpectedly, we found that breast tissue from BRCA1 mutation carriers harbors an expanded luminal progenitor population that shows factor-independent growth in vitro. Moreover, gene expression profiling revealed that breast tissue heterozygous for a BRCA1 mutation and basal breast tumors were more similar to normal luminal progenitor cells than any other subset, including the stem cell-enriched population. The c-KIT tyrosine kinase receptor (encoded by KIT) emerged as a key marker of luminal progenitor cells and was more highly expressed in BRCA1-associated preneoplastic tissue and tumors. Our findings suggest that an aberrant luminal progenitor population is a target for transformation in BRCA1-associated basal tumors .

http://basicmed.med.ncku.edu.tw/admin/up_img/981127-1.pdf

Aberrant luminal progenitors as the candidate target population for basal tumor development in BRCA1 mutation carriers

ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome.


 Introduction Addition of ovarian function suppression to conventional endocrine therapy alone in premenopausal women provides a survival benefit with moderate to high risk hormone-receptor positive breast cancer, especially who received chemotherapy Prediction of menstruation recovery after chemotherapy is important for deciding subsequent endocrine treatment and addressing fertility issues. Methods In the adding OFS after chemotherapy trial (ASTRRA), patients who resumed ovarian function up to 2 years after chemotherapy were randomized to receive either 5 years of tamoxifen or adding 2 years of OFS with tamoxifen. With these 1383 patients, we developed a model that predicts when patients recover menstruation within 3 years after chemotherapy using several variables including age, BMI, chemotherapy regimen and duration, serum E2 and FSH level. Results A total of 1017 patients data were used to develop prediction model and 366 patients data were used for external validation. In development group, 546 (53.6%) patients resumed menstruation during follow up period of 5 years. In multivariable analysis, younger age and AC based regimen without taxane were strong predictive factor for menstruation recovery. However predictive value of chemotherapy regimen was not constant over time. Therefore, we conducted another model with patients (n= 624) who did not recover menstruation within one year. In this patient group, predictive factors for menstruation recovery was age and serum E2 level at 6 months after chemotherapy. We also conducted a simplified scoring system to estimate change of recovery by using risk factors mentioned above. Conclusion Younger age is an important persisting factor predicting menstrual recovery after chemotherapy. Although chemotherapy regimen predicts shor-term menstrual recovery, over time, patient factors have more predictive influence on recovery. Recovery of serum E2 level would be important to predict subsequent menstruation recovery.
 Citation Format: Young Joo Lee, Woo C Noh, Seok J Nam, Byeong-Woo Park, Eun S Lee, Seock A Im, Yong S Jung, Jung H Yoon, Sung S Kang, Kyong H Park, Soo-Jung Lee, Min H Lee, Joon Jeong, Sung Y Kim, Hyun-Ah Kim, Se-Hwan Han, Wonshik Han, Min H Hur, Seonok Kim, Sei-hyun Ahn, Hee J Kim. Prediction of menstruation recovery timing in premenopausal breast cancer patients taking tamoxifen after chemotherapy: An ASTRRA substudy [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-10-07.

Abstract P2-10-07: Prediction of menstruation recovery timing in premenopausal breast cancer patients taking tamoxifen after chemotherapy: An ASTRRA substudy

Min Hee Hur

Papers

ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome.

Abstract P2-10-07: Prediction of menstruation recovery timing in premenopausal breast cancer patients taking tamoxifen after chemotherapy: An ASTRRA substudy