Collagen and fibronectin: threads linking obesity and breast cancer
Commentary

Collagen and fibronectin: threads linking obesity and breast cancer

Lesley G. Ellies1,2

1Department of Pathology, 2Moores Cancer Center, UC San Diego, La Jolla, CA 92093, USA

Correspondence to: Lesley Ellies. 9500 Gilman Drive, La Jolla, CA 92093, USA. Email: lellies@ucsd.edu.

Submitted Sep 13, 2016. Accepted for publication Sep 19, 2016.

doi: 10.21037/atm.2016.10.11


Evidence from epidemiological and clinical studies correlates obesity with an increased risk for postmenopausal breast cancer and a worse prognosis for breast cancer patients regardless of menopausal status (1). However, the cellular, molecular and structural mechanisms driving this process remain unclear. A potential structural mechanism is extracellular matrix (ECM) density, which is an independent risk factor for breast cancer (2,3). Myofibroblasts, the contractile, spindle-shaped, stress fiber-forming mesenchymal cells capable of producing copious amounts of ECM have emerged as a common hallmark of wound healing and tumor progression (4), leading to the generally held view that tumors are “wounds that do not heal”.

Seo et al. (5) have proposed that obesity induced structural changes enhance interstitial ECM stiffness, stimulating cancer cell growth and motility, thus linking obesity and the ECM in breast cancer progression. They provide evidence that changes in the quantity and quality (increased linearity) of interstitial collagen as well as alterations in fibronectin conformation in both intact and ovariectomized obese female mammary adipose tissue promote mechanosignaling and the malignant potential of breast cancer cells.

To extend the relevance of their findings in mouse experiments to humans, Seo et al. (5) analyzed tumor-free breast tissue from normal, overweight and obese women, confirming that levels of α-smooth muscle actin (α-SMA), a myofibroblast marker, correlated with ECM remodeling and inflammation. In addition, they found that tumors from obese patients exhibited more severe desmoplasia relative to tumors from lean patients, with increases in collagen fiber thickness as well as aligned fiber length. Other studies have shown that ECM fibers play an important role in organizing and facilitating streaming migration of carcinoma cells and macrophages in vivo, with movement often found to occur along ECM fibers aligned perpendicular to nearby blood vessels, potentially promoting metastatic spread (6,7).

Obesity-associated inflammation has also been correlated with breast cancer progression (8,9) with macrophages having either positive or negative effects in the tumor microenvironment depending on their functional state (10,11). We have shown in a murine model of postmenopausal breast cancer that the anti-tumor effects of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) do not occur through the GPR120 receptor which mediates some of their anti-inflammatory activity (12), suggesting that the TNF-α pathway is not a driver of luminal breast cancer in our model. Interestingly, nuclear accumulation of YAP/TAZ, the key nuclear relay of mechanical signals exerted by ECM rigidity and cell shape (13) is enhanced in tumors from obese patients (5). ω-3 PUFAs have recently been shown to ameliorate liver fibrosis by promoting YAP/TAZ degradation (14) and it is intriguing to speculate that beneficial effects of ω-3 PUFAs on breast cancers of obese individuals could be mediated via the inhibition of YAP/TAZ activity. This would be in keeping with results of a recent randomized clinical trial showing that ω-3 PUFAs decrease breast density in obese, but not overweight or normal weight postmenopausal women (15).

An inflammatory pathway that does appear to be causally related to obesity and breast cancer progression is the bacterially activated NLRC4 inflammasome and subsequent IL-1ß signaling, reported to act through adipocyte-mediated VEGFA expression and angiogenesis (16). The authors hypothesize that obesity-induced changes in the gut microbiome and endotoxaemia promote the NLRC4 inflammasome. Metformin inhibited obesity-associated tumor progression and was associated with a marked reduction in angiogenesis (16). An additional factor that was not considered, but could also play a role in these studies is ECM remodeling, since VEGFA can stimulate fibrosis (17) and metformin has been shown to inhibit excessive ECM deposition in white adipose tissue of obese mice (18).

The interrelationship between breast fibrosis as measured by mammographic density and increased cancer risk has been known for decades (19). However, this increased tissue density is not typically associated with chronic inflammation in the normal breast. Rather breast tissue density is a heritable trait that is influenced by multiple factors including menopausal status, weight and number of live births (3). It has been noted that although obese postmenopausal women have approximately a 30% increased risk of developing breast cancer compared with normal weight women (1), obese women tend to have less dense breasts due to the abundance of adipose tissue (20). As Seo et al. (5) demonstrate, changes in the quantity and quality of the ECM in the presence of obesity-induced chronic inflammation may be a critical causative factor linking obesity with breast cancer progression.

In order to predict the cohort of obese women at increased risk for breast cancer and to develop new approaches for prevention and treatment, the molecular pathways underpinning key clinical observations need to be defined. To fill the many gaps in our knowledge, more attention should be focused on the temporal sequence of molecular events occurring during the initiation and progression of breast cancer in obese subjects. Seo et al. (5) have provided the impetus to include ECM signaling as a fundamental driver of obesity-induced breast cancer.


Acknowledgement

Funding: This work was supported by the National Cancer Institute (grant number CA196853).


Footnote

Provenance: This is a Guest Commentary commissioned by Section Editor Bingrong Zhou, MD, PhD (Department of Dermatology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China).

Conflicts of Interest: The author has no conflicts of interest to declare.

Comment on: Seo BR, Bhardwaj P, Choi S, et al. Obesity-dependent changes in interstitial ECM mechanics promote breast tumorigenesis. Sci Transl Med 2015;7:301ra130.


References

  1. Carmichael AR. Obesity as a risk factor for development and poor prognosis of breast cancer. BJOG 2006;113:1160-6. [Crossref] [PubMed]
  2. Vachon CM, van Gils CH, Sellers TA, et al. Mammographic density, breast cancer risk and risk prediction. Breast Cancer Res 2007;9:217. [Crossref] [PubMed]
  3. Boyd NF, Dite GS, Stone J, et al. Heritability of mammographic density, a risk factor for breast cancer. N Engl J Med 2002;347:886-94. [Crossref] [PubMed]
  4. Rybinski B, Franco-Barraza J, Cukierman E. The wound healing, chronic fibrosis, and cancer progression triad. Physiol Genomics 2014;46:223-44. [Crossref] [PubMed]
  5. Seo BR, Bhardwaj P, Choi S, et al. Obesity-dependent changes in interstitial ECM mechanics promote breast tumorigenesis. Sci Transl Med 2015;7:301ra130. [Crossref] [PubMed]
  6. Roussos ET, Balsamo M, Alford SK, et al. Mena invasive (MenaINV) promotes multicellular streaming motility and transendothelial migration in a mouse model of breast cancer. J Cell Sci 2011;124:2120-31. [Crossref] [PubMed]
  7. Sharma VP, Beaty BT, Patsialou A, et al. Reconstitution of in vivo macrophage-tumor cell pairing and streaming motility on one-dimensional micro-patterned substrates. Intravital 2012;1:77-85. [Crossref] [PubMed]
  8. Feola A, Ricci S, Kouidhi S, et al. Multifaceted Breast Cancer: The Molecular Connection With Obesity. J Cell Physiol 2017;232:69-77. [Crossref] [PubMed]
  9. Howe LR, Subbaramaiah K, Hudis CA, et al. Molecular pathways: adipose inflammation as a mediator of obesity-associated cancer. Clin Cancer Res 2013;19:6074-83. [Crossref] [PubMed]
  10. Laoui D, Movahedi K, Van Overmeire E, et al. Tumor-associated macrophages in breast cancer: distinct subsets, distinct functions. Int J Dev Biol 2011;55:861-7. [Crossref] [PubMed]
  11. Zhou D, Huang C, Lin Z, et al. Macrophage polarization and function with emphasis on the evolving roles of coordinated regulation of cellular signaling pathways. Cell Signal 2014;26:192-7. [Crossref] [PubMed]
  12. Chung H, Lee YS, Mayoral R, et al. Omega-3 fatty acids reduce obesity-induced tumor progression independent of GPR120 in a mouse model of postmenopausal breast cancer. Oncogene 2015;34:3504-13. [Crossref] [PubMed]
  13. Dupont S, Morsut L, Aragona M, et al. Role of YAP/TAZ in mechanotransduction. Nature 2011;474:179-83. [Crossref] [PubMed]
  14. Zhang K, Chang Y, Shi Z, et al. ω-3 PUFAs ameliorate liver fibrosis and inhibit hepatic stellate cells proliferation and activation by promoting YAP/TAZ degradation. Sci Rep 2016;6:30029. [Crossref] [PubMed]
  15. Sandhu N, Schetter SE, Liao J, et al. Influence of Obesity on Breast Density Reduction by Omega-3 Fatty Acids: Evidence from a Randomized Clinical Trial. Cancer Prev Res (Phila) 2016;9:275-82. [Crossref] [PubMed]
  16. Kolb R, Phan L, Borcherding N, et al. Obesity-associated NLRC4 inflammasome activation drives breast cancer progression. Nat Commun 2016;7:13007. [Crossref] [PubMed]
  17. Karvinen H, Pasanen E, Rissanen TT, et al. Long-term VEGF-A expression promotes aberrant angiogenesis and fibrosis in skeletal muscle. Gene Ther 2011;18:1166-72. [Crossref] [PubMed]
  18. Luo T, Nocon A, Fry J, et al. AMPK Activation by Metformin Suppresses Abnormal Extracellular Matrix Remodeling in Adipose Tissue and Ameliorates Insulin Resistance in Obesity. Diabetes 2016;65:2295-310. [Crossref] [PubMed]
  19. Brisson J, Merletti F, Sadowsky NL, et al. Mammographic features of the breast and breast cancer risk. Am J Epidemiol 1982;115:428-37. [PubMed]
  20. Gillman J, Chun J, Schwartz S, et al. The relationship of obesity, mammographic breast density, and magnetic resonance imaging in patients with breast cancer. Clin Imaging 2016;40:1167-1172. [Crossref] [PubMed]
Cite this article as: Ellies LG. Collagen and fibronectin: threads linking obesity and breast cancer. Ann Transl Med 2016;4(Suppl 1):S50. doi: 10.21037/atm.2016.10.11