CD44 and
HMGA1 are well-known markers of cancer stem cells (CSCs) [
12]. Nakayama et al. found in axillary lymph node metastatic tissues of BC that, unlike
CD44 which is highly expressed in all CSCs,
HMGA1 is only highly expressed in certain specific CSC subgroups, and based on this, Nakayama et al. [
13] named it the "HMGA1 high-tumor stem cell subgroup". Differential gene analysis showed that the HMGA1 high-tumor stem cell subgroup specifically expresses characteristic genes such as
TMSB10 (encoding thymosin β10, closely related to the occurrence and development of various solid tumors [
14]),
CTSD (encoding cathepsin D, a star marker for poor prognosis in BC [
15]), and
LGALS1 (encoding soluble galectin-1, promoting the formation of inhibitory tumor immune microenvironment [
16]), suggesting it may be a risk factor for poor prognosis in BC. Furthermore, functional enrichment analysis showed that the differential gene set of the
HMGA1 high-tumor stem cell subgroup is significantly enriched in biological processes related to ribosome synthesis and transcription activation response RNA binding protein complex formation, the upregulation of these biological processes is considered to promote distant metastasis of BC [
17]. At the same time, in combination with ST, researchers found that compared to the HMGA1 high-tumor stem cell subgroup in primary tumors, the
HMGA1 high-tumor stem cell subgroup in lymph node metastasis has stronger proliferative potential, suggesting that a small number of
HMGA1-high tumor stem cells that spread to lymph nodes can form lymph node metastasis through massive proliferation [
13]. As a characteristic molecule of the
HMGA1 high-tumor stem cell subgroup—"HMGA1", a transcription factor, it regulates the transcription of target genes by altering chromatin structure and interacting with other transcription factors [
18]. Previous studies have shown that HMGA1 can promote the binding of EZH2 to cancer cell DNA, promote the formation of cytoplasmic chromatin fragments (CCF), and activate the cGAS-STING pathway, which can promote the production of inflammatory factors and the metastasis of BC [
19,
20]. Sgubin M et al. demonstrated in a mouse model that, after silencing
HMGA1, the metastatic activity of BC cells significantly decreased; this process was realized through the HMGA1/p27/stathmin axis, and the research results showed that after inducing HMGA1 depletion, the expression and activity of stathmin (an unstable phosphoprotein, which is overexpressed in metastatic tumors [
21]) on microtubules were downregulated, leading to a decrease in microtubule dynamics, resulting in reduced mobility of TNBC cells and thus reduced tumor metastasis. In addition, Sgubin et al. [
22] also found that HMGA1 plays an important role in tumor drug resistance, and after silencing
HMGA1, the sensitivity of BC cells to “paclitaxel” (paclitaxel is a drug used for TNBC treatment) increased. Wang et al. [
23] also found that in BC patients with high
HMGA1 expression, their survival rate is lower.
In conclusion, the existence of the HMGA1 high-tumor stem cell subgroup is closely related to tumor metastasis and drug resistance.