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Table 3 The impact of CAAs on breast cancer subtypes

From: Cancer-associated adipocytes: emerging supporters in breast cancer

Breast cancer subtype

Model

Impact of CAAs on breast cancer subtypes

Ref.

ER-positive

Co-culture model (MCF-7)

A direct co-culture between murine 3T3-L1-derived adipocytes and BC cells of various molecular subtypes induced an EMT phenotype and enhanced their proliferation, migration, and invasion capabilities.

[11]

ER-negative

Co-culture model (MDA- MB-231, MDA-MB-468)

ER-positive

Co-culture model (MCF-7)

CAA-conditioned medium increased the cell migration of both MCF-7 and MDA-MB-231 cells via IL-6 and CCL2.

[12]

ER-negative

Co-culture model (MDA-MB-231)

ER-positive

Co-culture model (ZR 75.1)

Mature adipocytes were able to stimulate the invasive capacities of murine and human BC cell lines that are either positive (ZR 75.1) or negative (SUM159PT, 67NR, 4 T1) for the ER. Coculture with adipocytes had no effect on ZR 75.1, 67NR or 4T1 proliferation in contrast to SUM159PT cells.

[14]

ER-negative

Co-culture model (SUM 159PT, 67NR, 4T1)

Luminal A

Co-culture model (MCF-7); human invasive ductal carcinoma sample

A total of 1126 and 1218 proteins were identified in MCF-7 and MDA-MB-231 cells, respectively. Among these, 85 (MCF-7) and 63 (MDA-MB- 231) had an average fold change > 1.5 following co-culture.

[16]

TNBC

Co-culture model (MDA-MB-231); human invasive ductal carcinoma sample

TNBC

Co-culture model (MDA-MB-231, MDA-MB-468); clinical samples in the dataset

Adipocytes could facilitate the pro-metastasis role in TNBC and non-TNBC via PLOD2-dependent way. PLOD2 expression was much higher in TNBC patients, compared to non-TNBC patients.

[24]

non-TNBC

Co-culture model (SK-BR-3); clinical samples in the dataset

ER-positive

Co-culture model (MCF-7, ZR-75-1)

The transition of adipocytes into more inflammatory CAAs resulted in proliferation-promoting effect in ER-positive BC cells such as MCF7 and ZR-75-1 but not in ER-negative cells; aromatase levels were upregulated in CAAs that might favor the growth of ER-positive BC cells.

[41]

ER-negative

Co-culture model (MDA-MB-231, Hs578T)

Not-given

Human BC samples

The expression of IL-6 was up-regulated in CAAs in human BC tissues.

ER-positive

Co-culture model (MCF-7, T47D)

In ER-positive cell lines, top upregulated genes showed significant enrichment for hormone receptor target genes. In triple-negative MDA-MB-231 cells, co-culture with adipocytes led to the induction of pro-inflammatory genes, mainly involving genes of the Nf-κB signaling pathway, and increased secretion of the pro-inflammatory interleukins IL-6 and IL-8.

[42]

TNBC

Co-culture model (MDA-MB-231)

Luminal A

Co-culture model (MCF-7)

Human adipocytes could enhance proliferation, migration and invasion abilities of MDA-MB-468 and MCF-7 cells after co-culture, and these effects were more profound in MDA-MB-468 cells compared with MCF-7, which are non-invasive cells.

[43]

TNBC

Co-culture mode (MDA-MB-468)

TNBC

Co-culture model (MDA-MB-231, MDA-MB-453)

Elevated secretion of CCL5 in adipocytes co-cultured with the TNBC cell lines heightened the EMT effect, thereby promoting tumor growth and lung and liver metastasis.

[51]

TNBC

Co-culture model (E0771); in vivo mouse orthotopic tumor model

Conditioned media from adipocytes supported E0771 cell proliferation and enhanced cell migration in vitro; adipocytes not only accelerated breast tumor growth, but also enhanced vascularization in vivo.

[54]

ER-positive

Co-culture model (MCF-7)

The co-culture media of human MCF-7 BC cells and human mature adipocytes increased the motility of MCF-7 cells through IGFBP-2.

[55]

Not-given

10 metastatic pathologic samples and 10 non-metastatic pathologic samples

Metastatic human breast tumors had higher levels of MMP-2 than did non-metastatic tumor tissue, whereas adipocytes around metastatic breast tumors had higher levels of IGFBP-2 than did adipocytes surrounding non-metastatic breast tumors.

ER-positive

In vivo zebrafish model (MCF-7, T47D)

Breast adipocyte increased the dissemination of ER-positive BC cells in the zebrafish model of metastasis, while dissemination of the more aggressive and metastatic BC cells such as ER-negative was unaffected.

[57]

ER-negative

In vivo zebrafish model (MDA-MB-231)

Not-given

Human invasive ductal carcinoma sample

CAAs isolated from 10 invasive breast carcinomas were pro-inflammatory and exhibited active phenotypes, including higher proliferative, invasive and migratory capacities.

[58]

TNBC

Co-culture model (MDA-MB-231, BT549)

CAAs could enhance migration and invasion of TNBC cells, while the effect of CAAs on ER-positive BC cells were limited.

[59]

ER-positive

Co-culture model (MCF-7, T47D)

Not-given

Human BC tissue sample

Elevated G-CSF expression in adipocytes was well correlated with activated Stat3 signal in cancer cells.

ER-negative

Co-culture model (M28N2, M27H4, M6)

Mammary adipose tissue-derived lysophospholipids promoted ER-negative mammary epithelial cell proliferation.

[63]

Luminal A

Co-culture model (MCF-7)

Proliferation, migration and invasion were increased in BC cells, which was most prominent for the highly invasive SUM159 cells and, to a lesser extent, for the less invasive MCF7 cells.

[78]

TNBC

Co-culture model (SUM159)

Not-given

Human invasive breast carcinoma sample

Collagen reorganization at the tumor-adipose periphery, as well as the positive relevance between PAI-1 and PLOD2 were found in invasive breast carcinoma, revealing a new stromal collagen network that favors tumor invasion and metastasis establish between BC cells and surrounding adipocytes at the tumor invasive front.

[80]

TNBC

Co-culture model (MDA-MB-231, Hs578t)

Adipocytes and adipocyte-derived conditioned media, but not pre-adipocytes, caused the mesenchymal MDA-MB-231 and Hs578t cells to form significantly more epithelial-like structures when compared to the typical stellate colonies formed in control 3D cultures. MCF7 cells had a less dramatic shift as they normally have a more epithelial-like structure in 3D culture.

[81]

Luminal A

Co-culture model (MCF7)

ER-positive

Co-culture model (T47D)

Adipocytes caused DOX resistance in all the cell lines studied, independently of the BC subtypes.

[104]

HER2-positive

Co-culture model (MDA-MB453, BT-474)

TNBC

Co-culture model (MDA-MB436, MDA-MB231, M-Wnt, E0771)

  1. Abbreviations: BC breast cancer; ER estrogen receptor; TNBC triple-negative BC; IL-6 interleukin 6; IL-8 interleukin 8; CCL2 chemokine ligand 2; CCL5 chemokine ligand 5; CAAs cancer-associated adipocytes; EMT epithelial-mesenchymal transition; IGFBP-2 insulin-like growth factor binding protein 2; G-CSF granulocyte colony-stimulating factor; DOX doxorubicin; PLOD2 lysyl hydroxylase 2; PAI-1 plasminogen activator inhibitor type 1