Breast cancer will affect 1 in 8 women in their lifetime. In most solid tumors, including breast cancer oxygen availability is limited due to the tumor outgrowing the vasculature.
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Also, the increase in diffusion distances in cancerous cells reduces the availability of oxygen. Unlike normal cells, cancerous cells are resilient in a hypoxic environment and so have developed ways to overcome to low availability of oxygen.
Conversely, severe and prolonged hypoxia can lead to necrosis. The presence of necrotic cell death is common within cancers, including breast cancer.
Hypoxia-inducible factors (HIFs) and the impact on breast cancer
HIF-1a and HIF-2a have previously been linked to breast cancer metastasis and poor patient survival. The expression of HIF-1a and HI-2a occur at different stages of mammary gland development and function.
Early studies have indicated that the selective inhibition of HIF-1a expression during development can lead to lactation failure whilst within breast cancer models, it has been shown to promote tumor growth.
An MCF-7 mouse model demonstrated the regulation and expression of both the subunits are not only dependent on oxygen availability.
Under hypoxic conditions, the subunits are stabilized. Meanwhile, in a malignant setting the activation of HIF- transcriptions leads to extracellular proteolytic activity, invasion, and angiogenesis.
On the other hand, the presence of hypoxic regions in a solid tumor means tumors can often resist conventional chemotherapy or radiotherapy.
HIFs can activate two key downstream processes through VEGF contributing to vascularisation and the expression of proteins regulating the switch from oxidative to glycolytic metabolism.
The difficulty in analyzing HIF inhibitors is their distinct lack of specificity. This is particularly common in the ER-/PR+ cancer group where there are already receptor blocking inhibitors used.
In vitro, using human breast cancer cell lines and the drug Ganetesip which blocks heat-shock protein 90 (HSP90) led to the degradation of HIF-1a. There was a marked decrease of 35% lower expression in addition to a reduced VEGF expression. This resulted in a reduction of tumor weight and growth.
Hypoxia and clinical outcome
Hypoxic lesions are present at each stage of tumor progression. Such as rapidly growing in situ lesions that have central necrotic regions.
It is often common with patients who have ductal carcinoma in situ (DCIS) if there is a high degree of necrosis and hypoxia there will likely be a shorter time to recurrence.
Breast cancer is such a disease that has intrinsically different subtypes with their prognostic outcome. It is interesting to note that estrogen-progesterone negative and a node-positive status have a lower mean pO2 and increased hypoxic and anoxic regions. The clinical importance of hypoxia in breast cancer pathology has also become increasingly well recognized in recent years.
If there is sustained exposure to hypoxia it often leads to a more aggressive phenotype. When exposed to a hypoxic microenvironment the cancerous cells can adopt new characteristics such as an increased angiogenic and migratory potential favoring invasion and metastasis.
Within breast cancer, it has been noted the hypoxic microenvironment favors a cancer stem cell niche which contributes to tumor initiation; treatment resistance and relapse. More recently, there has been evidence highlighting hypoxia having the ability to prime the metastatic niche through the recruitment of immune cells and tumor cells at distal sites.
The oxygenation of a tumor is crucial in therapeutic outcomes. It is strongly associated with chemotherapeutic resistance.
It is also established that hypoxic tumors do not respond as well to radiotherapy, primarily due to the need for oxygen to produce the reactive oxygen species needed for DNA damage. The presence of an estrogen receptor can predict the responsiveness to endocrine therapy, and its prognosis.
It is interesting to note that hypoxia can downregulate the estrogen receptor in several breast cancer lines; subsequently reducing the responsiveness to tamoxifen,
Targeting Hypoxia in the tumor microenvironment
Hypoxia is arguably one of the most attractive hallmarks of solid tumors due to its ability to mediate aggressive, metastatic and resistant disease.
Several approaches have been suggested namely hypoxia-activated prodrugs, gene therapy and specific targeting of HIFs.Hypoxic prodrugs have been designed in such a way so that they are activated in hypoxic tissue and therefore selectively kill the hypoxic tumor cells.
They are typically activated by the reduction of the prodrug by the cellular reductases. However, it is important to note that the downstream factors associated with hypoxia may be easier to target than hypoxia itself.
However, more recently physical activity has been discussed as a supportive factor for breast cancer mitigation. The effects of moderate aerobic exercise on tumor characteristics such as vascularisation and metabolism have been seen in the MDA-MB-231 cell line implanted into mice groups; which were randomly assigned wheel running.
A moderate exercise regime has been shown to increase intra-tumor vascularisation and normalization of the tissue microenvironmental. Conversely, the exercise-induced high concentration of HIFs is also associated with the normalization of the cancer microenvironment.
It has been thought to improve the oxygenation and removal of by-products. This is consistent with other studies where moderate exercise is associated with a 30-50% reduction in cancer mortality.
- Rausch, L. K., Netzer, N. C., Hoegel, J., & Pramsohler, S. (2017). The Linkage between Breast Cancer, Hypoxia, and Adipose Tissue. Frontiers in oncology, 7, 211. https://doi.org/10.3389/fonc.2017.00211
- Campbell, E.J., Dachs, G.U., Morrin, H.R., et al. Activation of the hypoxia pathway in breast cancer tissue and patient survival are inversely associated with tumor ascorbate levels. BMC Cancer19, 307 (2019). https://doi.org/10.1186/s12885-019-5503-x