NCOA1 Directly Targets M-CSF1 Expression to Promote Breast Cancer Metastasis

Li Qin1, Ye-Lin Wu2, Michael J Toneff1

  • 1Authors' Affiliations: Department of Molecular and Cellular Biology, Dan L. Duncan Cancer Center, Baylor College of Medicine;

Cancer Research
|April 29, 2014
PubMed

Insights

Nuclear coactivator NCOA1 promotes breast cancer metastasis by upregulating CSF1, enhancing macrophage recruitment. Silencing NCOA1 reduces metastasis, identifying a novel therapeutic target for breast cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Nuclear coactivator NCOA1 (SRC-1) overexpression is linked to breast cancer recurrence and endocrine therapy resistance.
  • The role of NCOA1 in mammary gland morphogenesis and carcinogenesis requires further investigation.

Purpose of the Study:

  • To investigate the impact of NCOA1 overexpression on mammary gland (MG) morphogenesis and carcinogenesis.
  • To elucidate the mechanisms by which NCOA1 influences breast cancer cell metastasis.

Main Methods:

  • Generation of MMTV-hNCOA1 transgenic [Tg(NCOA1)] mice.
  • Analysis of NCOA1's effect on MG morphology and tumor formation in transgenic models.
  • Mechanistic studies involving gene expression analysis, protein recruitment assays, and assessment of macrophage recruitment and metastasis.
  • Correlation analysis of NCOA1 and CSF1 levels with clinical parameters in a cohort of 453 human breast tumors.

Main Results:

  • NCOA1 overexpression did not alter MG morphology or tumor-forming capability in transgenic mice.
  • NCOA1 overexpression significantly increased circulating breast cancer cells and lung metastasis efficiency.
  • NCOA1 and c-Fos were recruited to the CSF1 promoter, upregulating CSF1 expression, enhancing macrophage recruitment, and promoting metastasis.
  • Silencing NCOA1 decreased CSF1 expression, macrophage recruitment, and breast cancer cell metastasis.
  • NCOA1 and CSF1 levels positively correlated with disease recurrence, higher tumor grade, and poor prognosis in human breast tumors.

Conclusions:

  • NCOA1 promotes breast cancer metastasis through an NCOA1/AP-1/CSF1 regulatory axis.
  • This axis enhances macrophage recruitment, contributing to metastatic progression.
  • The NCOA1/AP-1/CSF1 pathway represents a potential therapeutic target for inhibiting breast cancer metastasis.

Related Concept Videos

Induced Pluripotent Stem Cells01:06

Induced Pluripotent Stem Cells

Stem cells are undifferentiated cells that divide and produce different cell types. Ordinarily, cells that have differentiated into a specific cell type are terminally differentiated; however, scientists have found a way to reprogram these mature cells so that they dedifferentiate and return to an unspecialized, proliferative state. These cells are pluripotent like embryonic stem cells—able to produce all cell types—and are called induced pluripotent stem cells (iPSCs).
Somatic...
4.8K
Abnormal Proliferation02:23

Abnormal Proliferation

Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the...
4.0K
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
3.6K
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

1.5K
Cancer-Critical Genes I: Proto-oncogenes01:33

Cancer-Critical Genes I: Proto-oncogenes

Genes usually encode proteins necessary for the proper functioning of a healthy cell. Mutations can often cause changes to the gene expression pattern, thereby altering the phenotype.
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
9.1K
Cancer-Critical Genes I: Proto-oncogenes01:33

Cancer-Critical Genes I: Proto-oncogenes

6.1K