The Importance of Breast Adipose Tissue in Breast Cancer

Abstract

Adipose tissue is a complex endocrine organ, with a role in obesity and cancer. Adipose tissue is generally linked to excessive body fat, and it is well known that the female breast is rich in adipose tissue. Hence, one can wonder: what is the role of adipose tissue in the breast and why is it required? Adipose tissue as an organ consists of adipocytes, an extracellular matrix (ECM) and immune cells, with a significant role in the dynamics of breast changes throughout the life span of a female breast from puberty, pregnancy, lactation and involution. In this review, we will discuss the importance of breast adipose tissue in breast development and its involvement in breast changes happening during pregnancy, lactation and involution. We will focus on understanding the biology of breast adipose tissue, with an overview on its involvement in the various steps of breast cancer development and progression. The interaction between the breast adipose tissue surrounding cancer cells and vice-versa modifies the tumor microenvironment in favor of cancer. Understanding this mutual interaction and the role of breast adipose tissue in the tumor microenvironment could potentially raise the possibility of overcoming breast adipose tissue mediated resistance to therapies and finding novel candidates to target breast cancer.

Keywords: breast adipose tissue; breast cancer; breast development; risk factors; therapeutic intervention.

Figure 1

The role of adipose tissue in breast development. (A) Mature breast adipose tissue secretes leptin which is essential for ductal epithelial development. High levels of adiponectin inhibit this process. White adipose tissue (WAT) is essential for the formation of terminal end buds (TEBs) during prepuberty and puberty stages. After menarche, the breast starts to mature, and the duct starts its side branching, which requires WAT. (B) During pregnancy, WAT trans differentiates into pink adipose tissue (PAT). PAT has milk secretory potential. The process of trans differentiation from WAT to PAT is carried out by the transcription factor SPP1. Moreover, WAT is also essential for alveolar development during the lactation phase and also for the lactation process. During the phase of pregnancy and lactation, brown adipose tissue (BAT) trans differentiates to a basal myoepithelial phenotype helping in the alveolar development. Both trans differentiated cells revert to their original state after lactation with the aid of the transcription factor PPARγ. (C) There are two stages of breast involution (i) post-lactation and (ii) age-related. SFRP1 secreted by breast adipose tissue helps in these involution processes by the apoptosis of luminal epithelial cells. Furthermore, the epithelial cells are replaced by adipose tissue during the involution process.

Figure 2

Adipose tissue signaling in breast cancer. (A) Leptin, a major adipocytokine released by adipose tissue binds to the leptin receptor and activates the JAK2-STAT3 pathway leading to proliferation and stemness of BC cells. Leptin transactivated HER2 receptor in absence of its ligand via JAK2, which leads to BC survival. Leptin also activates the ER receptor in absence of estrogens and, furthermore, inhibits its proteasomal degradation. (B) Aromatase secreted by adipose tissue converts androgens to estrogens leading to an increase in BC risk. (C) Visfatin increases the MAPK-ERK pathway through an unknown receptor thereby increasing BC proliferation. Activated MAPK also activates STAT3 signaling. (D) FABP4 expression is transcriptionally activated by the ERK-Ets1 pathway. Upon activation, FABP4 increases proliferation and migration of BC cells by nuclear accumulation of PPARγ and SREB2. Furthermore, FABP4 translocates to the cytoplasm where it binds to RA and, therefore, leads to cell differentiation. (E) Adiponectin increases the insulin signaling, glucose uptake, decreases glycogen synthesis and inhibits STAT3 and NFκB mediated signaling leading to the inhibition of BC survival and progression. (F) SFRP1 signaling through the integrin receptor inhibits pro-inflammatory cytokines, TGFβ and Wnt signaling, thereby inhibiting BC progression.

Figure 3

BC risk factors and prognostic factors and the role of adipose tissue. (A) Early menarche and late menopause increase the risk of BC by increasing the exposure of breast cells to estrogen hormones. Breast adipose tissue secretes aromatase which converts androgen to estrogen further complicating the scenario. (B) Breast adipose tissue secretes SFRP1 which helps in post-lactation involution age-related breast involution. Involution involves the inflammation process leading to apoptosis of epithelial cells. High levels of pro-inflammatory molecules secreted by breast adipose tissue lead to partial involution which increases the risk of BC. (C) Microcalcification is a predisposing factor for BC. Microcalcifications due to fat necrosis resemble malignant microcalcifications further complexifying prognosis of BC. Furthermore, SPP1 secreted by breast adipose tissue changes the fate of adipose derived stem cells (ADSC) to osteogenesis, increasing BC risk. Moreover, breast adipose tissue increases the inflammatory process accompanying mineralization. (D) During BC progression, BC cells signal lipolysis of surrounding adipose tissue to meet the energy requirement of BC. Adipose tissue releases lactate, pyruvate and free fatty acids. WAT also starts to express UCP-1, thereby trans differentiating to BAT and exhausting the energy source of the body. This leads to cachexia and eventually death. Around 30–50% of cancer-associated deaths are due to cachexia. (E) Obesity is a worldwide problem and known to increase BC risk. High adipose tissue increases the inflammatory process and hypermethylation (resulting in inhibition) of tumor suppressor genes. Obesity also increases the expression of estrogen and estrogen receptors in postmenopausal women, enhancing the risk of BC.

Figure 4

Interaction between BC cells and adipose tissue in the BC microenvironment. Breast adipose tissue secretes various molecules (green) which increase BC survival, proliferation, migration, angiogenesis and metastasis. These secretomes also help BC cells in evading chemotherapy mediated apoptosis and increase the survival of residual cancer cells after chemotherapy. BC cells also secrete cytokines and chemokines which signal lipolysis of adipose tissue, changing the secretory phenotype of adipose tissue to a cancer-associated phenotype. The cancer associated adipose tissue aids in BC survival by releasing inflammatory cytokines, proteases and providing the energy source in the form of free fatty acids. Studies have identified various approaches to target the crosstalk between BC cells and adipose tissue (indicated in red). By targeting the differentiation of pre-adipose tissue to mature adipose tissue, which can be performed by overexpressing adipogenesis regulatory cells (Aregs stop this differentiation), PDGFRα (changes the fate of pre-adipose tissue to extracellular matrix) or by treatment with Sulforaphane (which stimulates the regeneration of pre-adipocytes and inhibits its differentiation to mature adipocytes). Furthermore, the inhibition of fatty acid transporter 4 (BMO309403) inhibits the transfer of energy from adipose tissue to BC cells. Moreover, the inhibition of CD36 by monoclonal antibody against CD36 leads to the inhibition of fatty acid uptake by BC cells. Another study showed that increasing the expression of PPARγ in BC cells could lead to trans differentiation of BC cells into adipose tissue, thereby inhibiting BC angiogenesis.